Prescribing geroprotectors – the future of aging prevention?

Highlights:

• Geroprotectors are the substances that could protect from aging or slow down the aging mechanisms
• Two main families of geroprotectors are calorie restriction mimetics such as metformin and senolytics such as dasatinib with quercetin
• Over the counter drugs such as aspirin or melatonin have geroprotective potential

Introduction

Aging is a set of processes that affects the whole organism starting from our molecules and ending in the physiology of our body. Aging is responsible for the progressive deterioration in physical and mental function and disease development. The European Union consortium ICARE4EU reported that 50 million EU residents, and over 60 % of the over 65-year-olds, deal with more than one disease (multimorbidity). The standard medical system still treats each disease individually, resulting in problematic and potentially risky drug-drug and drug-disease interactions that negatively impact the patients health, called polypharmacy.

Geroprotectors mechanism of action

The world population is quickly aging with the grim vision of economic collapse in developed countries looming around the corner. Therefore, besides disease treatment, prevention and aging studies known as gerontology become a necessity to improve the longevity of the aging population (1, 2). There are common hallmarks of aging for many age-associated diseases, which gives the hope that there is a potential to treat multiple diseases with the same drug. These drugs are known as geroprotectors and might be the future of multimorbidity treatment that could solve the problem of polypharmacy (2).

Gerontology is a study of the social, cultural, psychological, cognitive, and biological aspects of aging. It differs from geriatrics; a medical field focused on treating existing diseases in older adults. The founder of scientific gerontology is a biologist and Nobel laureate Ilya Metchnikoff (3), who also coined the word "geroprotector" to describe possible agents that could protect from aging or slow down the aging mechanisms. In general, a substance is called a geroprotector when it has the ability to increase the lifespan of the model organism (1). Scientists have already found over 250 such substances, the current list of which is in the Geroprotectors.org database (4). Most of them, unfortunately have not been yet tested well in human models. The status of the human clinical trials can be checked on the tool called Rejuvenation Roadmap.

Geroprotectors have the ability to postpone the multiple tissues’ dysfunction connected with aging, delay multimorbidity, and improve resilience by impacting the aging mechanisms such as senescence, autophagy, and inflammation. They can improve the health span of multiple systems, including cardiovascular, cognitive, neuromuscular, and immune. Geroprotectors were proven to slow the development of such issues as cataracts, frailty, sarcopenia, osteoarthritis, osteoporosis, atherosclerosis, and Alzheimer’s diseases in mice (5).

Most aging mechanisms are remarkably conserved in the animal kingdom. In humans, aging processes relate to the appearance of age-related diseases such as diabetes, cancer, neurodegeneration, and cardiovascular disease. So potential anti-aging geroprotector should be linked to treating at least one of these age-related diseases. The well understood biochemical and physiological pathways associated with aging include Insulin-like Growth factor (IGF)‑1 signaling, impact of reactive oxygen species (ROS), senescence‑promoting genes, sirtuins, Forkhead Box – O (FOXO) transcription factors, heat shock proteins, and target of rapamycin (TOR). These pathways are the aim of geroprotectors (6-9).

Calorie restriction mimetics

The calorie restriction mimetics (CRMs) targeting TOR enzyme could be the first example of geroprotectors (7, 9). The nutrient–sensing TOR pathway can be inhibited by dietary calorie restriction, which in return induces sirtuins, reduces free radical formation, and increases insulin sensitivity. All these mechanisms delay the development of age-related diseases and functional decline and improve stress resistance. Unfortunately, calorie restricting diet (the reduction of average caloric intake) can be challenging to follow, and here is where CRMs such as metformin, could suffice (9). Metformin is a biguanide and glucose-lowering agent which is successfully used as a first-line treatment for type 2 diabetes.  It acts as CRM by reducing hepatic gluconeogenesis, promoting glucose uptake in peripheral tissues and fatty acid oxidation. Metformin has seemed to reduce the incidence of cancer or cardiovascular disease and increase survival in people with diabetes (10-12).

Rapamycin is another drug that inhibits TOR, by AMPK dependent and independent mechanisms, to inhibit translation and activate autophagy, leading to extension of lifespan. In clinical practice, rapamycin is an immune suppressor in patients undergoing transplants. Its use prevents new tumor formation and leads to regression of already existing tumors (2, 13).

Senolytics

Senolytics such as dasatinib with quercetin and fisetin are drugs, which can selectively induce cell death in senescent cells (cells that cannot divide anymore) by targeting their specific survival pathway. Senescent cells are required to maintain the structure, function, and regeneration of tissues. They are accumulated with age and are suggested to drive age-associated dysfunction in multiple tissues. Senolytics can be administered intermittently to eliminate newly formed senescent cells periodically, and this form of treatment may have fewer side effects and be more cost-effective. They have been proven to reduce inflammation and alleviate frailty in humans as well (14).

Dasatinib is a tyrosine kinase inhibitor used to treat leukemia which has little or no senolytic activity on its own but gains it in combination with quercetin. Quercetin, as well as fisetin, are flavonoids present in plants and fruits with antioxidant features. They are anticipated to be safer options to dasatinib. However, the dose and time of administration to obtain senolytic activity is higher than that which is safely recommended, and appropriate studies are required. Quercetin also has low senolytic activity itself and has to be administered with dasatinib. Sadly, most senolytics, except few natural compounds, have undesired or potentially harmful side effects (2, 15).

Can over-the-counter drugs be geroprotectors?

Some over-the-counter drugs have been researched as possible geroprotectors as well. Few examples are:

• anti-inflammatory drugs such as common aspirin and ibuprofen,
•  sleep-regulating hormone melatonin
•  supplements such as spermidine or nicotinamide mononucleotide (NMN).

Aspirin was found to postpone aging by interfering with reactive oxygen species production, cytokine response processes and by blocking glycooxidation reactions in fruit fly and nematode C. elegans. In humans, aspirin might be one of the most applicable future anti-aging drugs due to its low costs and simplicity of treatment. It was also already thoroughly investigated regarding the prevention of cardiovascular disease and cancer. Nevertheless, the geroprotective effect remains to be researched (16).

Spermidine is a polyamine produced endogenously in the human body, which can also be obtained from food. Polyamines are necessary for cell functions such as apoptosis, cell proliferation and differentiation, nucleic acid and protein synthesis, and protecting against oxidative damage. Spermidine supplementation was also proven to be cardioprotective, neuroprotective and anti-tumorigenic, and in multiple species, including Drosophila, C. elegans, and mice it promotes longevity. A population-based study conducted amongst 829 Italian participants showed that higher spermidine intake was connected with reducing all-cause mortality (17).

Melatonin or N-acetyl-5-methoxy-tryptamine is the main pineal hormone, critical for regulating sleep and circadian and seasonal changes. With age the night production of melatonin decreases. There are several reports showing that melatonin has anticarcinogenic and antitumor potential as well (18).

In 2017 the researchers identified that the metabolite NAD+, present naturally in every human cell, has a critical role in DNA repair through regulating the protein-to-protein interactions. In mice, the NAD+ precursor known as nicotinamide mononycleotide (NMN) was proven to boost the ability to repair DNA damage caused by aging or radiation exposure in the cell and activate sirtuins. NMN is currently in human clinical trials at Brigham and Women’s Hospital (19).

There is still no longevity elixir

Although the geroprotectors discovery is a popular biomedicine trend, there are still no prescribable geroprotectors per se on the market. There is a lack of a unified concept of aging mechanisms and not enough available research of geroprotectors in humans (1). Despite promising evidence, there is still a long road ahead to fully understand the treatment of age-associated multimorbidity. There are still many gaps and challenges that must be addressed to make gerontology and geroprotective medicine the future of geriatrics (2). Moreover, research shows that geroprotectors’ unfortunately may work differently in specific tissues or in response to different inducers of accelerating aging, suggesting that the idea of one drug for many diseases may not be so easy to implement (2). It is essential to know that every hypothetical geroprotector usage may have side effects, and many of these drugs may extend lifespan by means of hormetic effect: the conditions in which relatively toxic substances may have beneficial effects (16).

References

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

2.            Morsli S, Bellantuono I. The use of geroprotectors to prevent multimorbidity: Opportunities and challenges. Mech Ageing Dev. 2021;193:111391.

3.            Metchnikoff É, Mitchell P. The prolongation of life; optimistic studies by Élie Metchnikoff. New York: GP Putnam’s sons. 1910.

4.            Moskalev A, Chernyagina E, de Magalhaes JP, Barardo D, Thoppil H, Shaposhnikov M, et al. Geroprotectors.org: a new, structured and curated database of current therapeutic interventions in aging and age-related disease. Aging (Albany NY). 2015;7(9):616-28.

5.            Trendelenburg AU, Scheuren AC, Potter P, Muller R, Bellantuono I. Geroprotectors: A role in the treatment of frailty. Mech Ageing Dev. 2019;180:11-20.

6.            Smith HJ, Sharma A, Mair WB. Metabolic Communication and Healthy Aging: Where Should We Focus Our Energy? Dev Cell. 2020;54(2):196-211.

7.            Antikainen H, Driscoll M, Haspel G, Dobrowolski R. TOR-mediated regulation of metabolism in aging. Aging Cell. 2017;16(6):1219-33.

8.            Watroba M, Szukiewicz D. The role of sirtuins in aging and age-related diseases. Adv Med Sci. 2016;61(1):52-62.

9.            Chiba T, Tsuchiya T, Komatsu T, Mori R, Hayashi H, Shimokawa I. Development of calorie restriction mimetics as therapeutics for obesity, diabetes, inflammatory and neurodegenerative diseases. Curr Genomics. 2010;11(8):562-7.

10.          Bulterijs S. Metformin as a geroprotector. Rejuvenation Res. 2011;14(5):469-82.

11.          Piskovatska V, Stefanyshyn N, Storey KB, Vaiserman AM, Lushchak O. Metformin as a geroprotector: experimental and clinical evidence. Biogerontology. 2019;20(1):33-48.

12.          Zajda A, Huttunen KM, Sikora J, Podsiedlik M, Markowicz-Piasecka M. Is metformin a geroprotector? A peek into the current clinical and experimental data. Mech Ageing Dev. 2020;191:111350.

13.          Speakman JR, Mitchell SE. Caloric restriction. Mol Aspects Med. 2011;32(3):159-221.

14.          Kirkland JL, Tchkonia T, Zhu Y, Niedernhofer LJ, Robbins PD. The Clinical Potential of Senolytic Drugs. J Am Geriatr Soc. 2017;65(10):2297-301.

15.          Proshkina E, Shaposhnikov M, Moskalev A. Genome-Protecting Compounds as Potential Geroprotectors. Int J Mol Sci. 2020;21(12).

16.          Lushchak O, Piskovatska V, Strilbytska O, Kindrat I, Stefanyshyn N, Koliada A, et al. Aspirin as a Potential Geroprotector: Experimental Data and Clinical Evidence. Adv Exp Med Biol. 2021;1286:145-61.

17.          Raj SD, Fann DY, Wong E, Kennedy BK. Natural products as geroprotectors: An autophagy perspective. Med Res Rev. 2021.

18.          Anisimov VN, Popovich IG, Zabezhinski MA, Anisimov SV, Vesnushkin GM, Vinogradova IA. Melatonin as antioxidant, geroprotector and anticarcinogen. Biochim Biophys Acta. 2006;1757(5-6):573-89.

19.          Li J, Bonkowski MS, Moniot S, Zhang D, Hubbard BP, Ling AJ, et al. A conserved NAD(+) binding pocket that regulates protein-protein interactions during aging. Science. 2017;355(6331):1312-7.

‍