Is anti-ageing drug discovery becoming a reality?

KEYWORDS:

• Aging
• longevity
• geroprotector
• gerosupressor
• senolytics
• hormetin

1. Introduction

Geroprotectors are pharmacological agents that can decrease the rate of aging and extend lifespan. The first attempt of life extension via pharmacological treatment was carried out by Thomas Gardner on mice [1,2] and flies [3,4]. Later, the Free Radical Theory of Aging by Denham Harman paid new attention to geroprotecton, having applied antioxidant radioprotectors as geroprotectors [5]. Some authors use an alternative term, anti-aging drugs [6,7].

Our curated database, geroprotectors.org, includes 259 compounds that extend lifespan at least in one concentration in 13 model organisms from yeast to human, obtained from 2408 literature references [8]. There is also the project DrugAge database, which contains more than 400 compounds tested on lifespan [9]. Potential geroprotectors are not only synthetic compounds but can also be ingested with food or excreted by symbiotic intestinal microbiota (for example, butyrate, spermidine, vitamin K2, urolithin A).

Importantly, aging is not recognized as a disease [10] and there are no clinical trials for geroprotective properties in itself. Therefore, there are no clinically proven human geroprotectors, so we can only discuss potential candidates.

2. Selective criteria and classification of geroprotectors

For there to be the successful translation into the clinic, we cannot be limited to one or two criteria such as with life extension. The goal for human application should be to increase healthspan as well, where there is a ‘ period of life spent in good health, free from the chronic diseases and disabilities of aging’ [11]. Indeed, the term ‘health’ in relation to aging could be considered as the capacity to tolerate and adapt to changing perturbations (robustness, resilience) [12].

For this purpose, we have proposed a set of primary and secondary selection criteria for a potential geroprotector [13].

2.1. The primary criteria that should be met

• Life extension in experiments with wild type animal models. Theoretically, based on the meaning of the term, the geroprotector should prolong the life of the model beyond the intact species’ maximum lifespan, protecting it from one or more mechanism of aging. However, in practice, at best, we are talking about increasing the lifespan by tens of percent. Therefore, it is more accurate to talk about gerosuppressors, and not geroprotectors.

• Improvement of molecular, cellular, and physiological biomarkers to a younger state or slow down the progression of age-related changes in human.

• Most potential geroprotectors are preventive only when applied at relatively high concentrations. The lifespan-extending dose should be several orders of magnitude less than the toxic dose.

• Minimal side effects at the therapeutic dosage at chronical application.

• The potential benefit of taking the geroprotector may come after a long period of time. Potential geroprotectors should initially improve some parameters of health-related quality of life: physical, mental, emotional, or social functioning of the person. This can serve as the basis for their chronical use.

2.2. Secondary selection criteria for potential geroprotector

• The target or mechanism of action of the geroprotector that extends the lifespan of the model should be evolutionarily conserved.

• Reproducibility of geroprotective effects on different model organisms increases the possibility that effects will also be discovered in humans, even in the absence of a known conserved target.

• Candidate geroprotectors should be able to delay the progress of one or several age-associated diseases in human.

• Potential geroprotectors should increase organism resistance to unfavorable environmental factors.

Aging can be considered as the exponential shrinkage of homeodynamic capacity leading to the onset of age-related diseases and death [14].

We have theorized that the classification of geroprotectors be based on the concept of homeostasis [15] or, more accurately homeodynamics. These can be separated into four groups:

As such, the first group of geroprotectors can suppress the consequences of homeodynamic disruption. From this broad point of view, many antidiabetic, anti-arrhythmic, lipid-lowering, cardiovascular and antihypertensive drugs can be considered as such a type of geroprotector.

The second group enhances systems that ensure homeodynamics, that can be achieved by inducers of stress-resistance, mimetics of caloric restriction, immunomodulators.

The next group of potential geroprotectors provides the neutralization of damaging factors that causes disruption to homeodynamics. For example, ROS scavengers, heavy metal chelators, matrix metalloproteinases inhibitors, senolytics, anti-mutagens, anti-amyloid or anti-glycation agents.

The last group are suppressors of excessive homeodynamics reactions that lead to even greater loss of homeostasis. Excessive activation of damage-induced adaptive mechanisms, such as PARP1-dependant DNA breaks sensing, HIF-1 hypoxia response, innate immunity, and inflammation, cellular senescence or autoimmunity are components of vicious cycles, that accelerate the aging speed and provoke aging-related diseases.

Aging is also the gradual accumulation of cellular and tissue damage. There are several universal hallmarks of aging including [16]: DNA damage, ROS-induced lesions, mitochondrial dysfunction, epigenetic changes, proteostasis impairment, stem cell exhaustion and immunosenescence. The cell and the body delay damage accumulation in several ways: a) by preventing lesions, b) by repairing it or c) by removing and replacin unrepairable structures. Aging is primarily the dysregulation of these systems aimed at preventing, repairing and regenerating. Therefore, potential geroprotectors can be divided into subclasses according to these aging-preserving mechanisms. The same compound can affect several mechanisms. Potential anti-aging therapies may be based on completely different approaches that could be combined. Many of the approaches mentioned above are unattainable in the state of the art, but some of them are potentially available.

3. Ongoing clinical trials of potential geroprotectors

In particular, aging is accompanied by the accumulation of toxic products of peroxidation of polyunsaturated fatty acids, which are involved in the development of various age-related diseases [17]. Deuterium-reinforced linoleic acid lowers lipid peroxidation and mitigates cognitive impairment in the mouse model of Huntington’s disease [18]. A randomized clinical trial with dPUFA has also commenced for its use in patients with Friedreich’s ataxia [19].

During aging, amyloid aggregates of proteins accumulate in various organs and tissues, such as the pancreas, heart, and brain [20]. While there are several recent therapeutic trials of anti-amyloid interventions, the anti-β-amyloid clinical trials have not shown cognitive improvement [21,22].

Of note, the first clinical trial positioning pharmacological approaches to slowing down aging, Target Aging with Metformin (TAME) has been approved by the FDA [23,24]. Metformin is an intensively studied drug [25]. However, the application of metformin as a preventive agent in people without diabetes is still being discussed. Interestingly, at least one review [26], has proposed that in people without diabetes, metformin does not reduce the risk of developing diseases, such as cardiovascular.

Urolithin A occurs through the influence of microbiota on ellagic acid, a component of polyphenolic-rich plant foods, which stimulates mitophagy and improves muscle health in old animals. It also increases lifespan in C. elegans and in old mice [27]. Urolithin A demonstrates safety and bioavailability in elderly people, while it modulates acylcarnitines in plasma and the expression of skeletal muscle mitochondria genes, that researchers believe can help to treat sarcopenia [28].

Of mainstream importance is the key role of senescent cells in aging and age-related diseases [29]. The Mayo Clinic have published the results of their first pilot study using dasatinib and quercetin in combination as senolytics to treat idiopathic pulmonary fibrosis. This was a small pilot study that did not have a control or a placebo group [30]. In this clinical study, the senescence associated secretory phenotype, pulmonary function and fragility index of the subjects did not change. At the same time, some physical functions of the subjects improved significantly including: endurance when walking, speed of movement and keeping the body in an upright position while standing at a chair [30,31]. Unity Biotechnology, which previously achieved life extension by removing senescent cells in mice, presented a Phase I clinical trial report of senolytic UBX0101 in patients with osteoarthritis of the knee. The study evaluated pain, and the drug showed mixed conclusions in different groups [32].

TORC1 is recognized as one of the main regulators of cellular aging, and the suppression of its activity extends the life of many model organisms [33]. A clinical trial revealed that a low-dose combination of a catalytic (BEZ235) and an allosteric (RAD001) TORC1 inhibitor was safe and associated with a decrease in the rate of infections reported by elderly subjects for a year after study drug initiation. There was also an observed up-regulation of antiviral gene expression and an improvement in response to influenza vaccination in this treatment group [34]. Also notably, a clinical trial of RTB101, an oral, selective TORC1 inhibitor was stopped at Phase 3 in clinically symptomatic respiratory illness because it did not meet the primary endpoint [35].

4. Expert opinion

Geroprotectors, as drugs that can slow down aging and promote healthspan, are attracting more attention. Even though about 400 compounds are known to extend life of the laboratory model organisms, few of them meet the criteria of potential geroprotectors and clinical studies of potential geroprotectors are very rare. Some of these compounds are already FDA approved, and this gives hope for an increase in the number of clinical trials for multimorbid conditions associated with aging. There are also some ongoing clinical trials of potential geroprotectors, that can extend lifespan in model organisms and these may further the clinical investigations of age-related diseases such as is the case with the compounds dPUFA, metformin, everolimus, urolithin A, and the senolitics.

Despite many known aging-preventive mechanisms, most classes of potential geroprotectors are poorly studied, even at the preclinical level. For any far-reaching conclusions, there is not enough data in compliance with the necessary primary criteria for geroprotectors. For example, it may turn out that the number of side effects outweighs the potential benefits in the long run. This is highly likely, since the more effective the drug, the more possible it will have unacceptable side effects. Most of the geroprotector examples only currently increase lifespan slightly or only in one gender.

There are potential geroprotectors that have promisingly proven themselves in models but are waiting for their placebo-controlled, blind, multicenter clinical studies with biomarkers of human aging and mortality data. However, the absence of a generally accepted panel of biomarkers of human aging makes preclinical studies of potential geroprotectors currently difficult to check in a clinic. When choosing a potential candidate for translation from preclinical to clinical studies, it is worth considering the cost, absorption, bioavailability and microbiota transformation of the substance.

Even though some potential geroprotectors are already on the way, we need to look for stronger geroprotectors and their synergistic combinations.

Since the goal of the geroprotector is to increase healthspan, ideally, treatment should begin before any chronic diseases appear and delay the onset of the age-related chronic disease [26]. Nevertheless, getting permission for such a study is probably more difficult.

So far, it is also important to note that it’s fair to talk not about geroprotectors, but about gerosuppressors, since nowadays we know how to prevent or slow down some manifestations of aging but not how to reverse it.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The study was funded within the framework of the state task on the theme Development of gerorotective and radioprotective drugs, state registration № АААА-А19-119021590022-2, and complex UrB RAS Programme № 18-7-4-23 A combination of factors of different nature (low temperature, lack of lighting, restrictive diet, and geroprotector) to maximize the lifespan of Drosophila, state registration № АААА-А18-118011120008-3.