Keywords

1 Introduction

Over the past several decades, human life expectancy was significantly raised across all developed countries. This demographic trend is, however, not accompanied by the same extension of healthspan (Crimmins 2015). This is because the aging process per se is the main risk factor for most chronic diseases affecting the elderly, including immunosenecence, atherosclerosis, cardiovascular disorders, type 2 diabetes, hypertension, osteoporosis, sarcopenia, frailty, arthritis, cataracts, Alzheimer’s and Parkinson’s diseases and most cancers (Jaul and Barron 2017). Therefore, slowing down the aging rate is believed to be more effective in delaying aging-associated chronic conditions than treating them one by one, which is the conventional approach in a current disease-based paradigm. Thus, the development of efficient means for age-related disease prevention, healthspan extension and compression of morbidity to the very last years of a person’s lifespan only becomes a priority task for policy makers and research organizations (Yabluchanskiy et al. 2018). In a translational perspective, a key component of research activities aimed at healthspan extension is the achievement of so-called “optimal longevity”. The condition of optimal longevity is referred to as “living long, but with good health and quality of life” (Seals et al. 2016) and includes improved functioning and independence during the later stages of life.

Currently, the research activity aimed at improving the healthspan is primarily focused on slowing down the molecular and cellular mechanisms underlying aging. These studies are focused on investigating the processes commonly mediating aging such as impaired proteostasis, stem cell maintenance and cell energy sensing, mitochondrial dysfunctions, deregulated growth and stress resistance pathways, cellular senescence, and also oxidative stress and inflammatory responses (Kumar and Lombard 2016; see also Fig. 27.1 for illustration).

Fig. 27.1
figure 1

Summary of various factors that may contribute to aging. Dysregulation of nutrient-sensing pathways, mitochondrial dysfunction, loss of proteostasis, stem cell attrition, accumulated DNA damage, reduced autophagy, accumulation of senescent cells, and increased sterile inflammation are some important pathways thought to drive aging. This figure is reproduced from an Open access article by Kumar and Lombard (2016), which is published under a Creative Commons Attribution License

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Since diet and physical activity are essential modifiable risk factors for most age-related chronic disorders, including type 2 diabetes, cardiovascular disease and cancer, the promotion of healthy diet and exercise regimes is an important goal for a public health policy oriented toward healthy aging (Sowa et al. 2016). In addition to modifiable life-style factors, great expectations in this regard are related to the use of various pharmacological interventions shown to be pro-longevity in different experimental models, from worms to rodents. Therapeutic modalities, which are based on these interventions, are being increasingly developed and investigated now in pre-clinical and clinical trials to determine whether they have potential for human healthspan extension (Vaiserman and Marotta 2016; Vaiserman and Lushchak 2017). These pharmacological interventions have been shown to reduce chronic inflammation, prevent cardiovascular disease, and also slow down certain functional declines. Moreover, they were found to be able to inhibit carcinogenesis by interfering with various aspects of cell metabolism, apoptosis, proliferation, and also angioneogenesis (Figueira et al. 2016). Most promising anti-aging pharmaceuticals include, among others, synthetic drugs such as rapamycin, metformin, aspirin and statins (Vaiserman et al. 2016). High hopes are also placed now on compounds derived from natural sources, e.g. polyphenols such as resveratrol, quercetin, curcumin, catechin and epigallocatechin gallate (Martel et al. 2019) and bioactive compounds from seaweeds such as fucoxanthin (Muradian et al. 2015). In addition, present-day anti-aging treatment modalities include removal of senescent cells, change in gut microbiota, transfer of blood components from young donors, and also gene- and cell-based therapies (Partridge et al. 2018). These therapeutic modalities have, however, reached the stage of preclinical testing only, so their effectiveness and safety has not been confirmed in clinical trials so far.

In considering healthspan-promoting effects of pharmacological agents, some theoretical considerations have to be taken into account. In particular, within the reductionist paradigm which is still accepted by many experts in the field, the organism is regarded as a totality of relatively independent mechanical components and processes. From this point of view, interventions aimed at expanding the human healthspan are considered as those which do not differ significantly from those used in car repairing. Within this paradigm, it is assumed that the aging rate may be slowed by affecting separate cellular and molecular pathways involved in specific aspects of the aging process. However, accumulated research evidence indicates that such a view is too simplistic. Since aging is a very complex trait influenced by multiple genetic pathways and environmental factors, it seems quite difficult, if not impossible, to develop pharmacological interventions able to effectively slow aging and extend healthspan by targeting only single molecular pathways (Vaiserman 2014). One potential solution to this problem is using more complex (“holistic”) therapeutic modalities (e.g. drug cocktails) to simultaneously target multiple molecular cascades related to aging.

The main aim of this chapter is to discuss whether pharmacological interventions approved by the U.S. Food and Drug Administration (FDA) and other regulatory agencies for treatment of particular diseases and shown to demonstrate pro-longevity activities in experimental models may have potential for human healthspan extension as well. Several products currently regulated by FDA as dietary supplements (e.g. vitamins and melatonin) but thoroughly investigated in clinical trials and widely discussed in the context of anti-aging medicine will be also reviewed.

2 Could Aging Be Targeted by Drugs?

At present, regulatory agencies across the world, such as the FDA, do not recognize aging as a feasible target for the pharmacological intervention (Prattichizzo et al. 2019). Nevertheless, the development of drugs specifically targeted at age-related pathologies is one of the most actively developing biomedical fields. In the search for druggable molecular targets, experimental approaches based on applying gain- or loss-of-function phenotypes are widely used to identify genetic pathways which are potentially suitable for anti-aging intervention (López-Otín et al. 2013; Moskalev et al. 2014). Even though identification of processes underlying aging is obviously a challenging task because these processes are extremely complex, significant progress has been achieved in this field over the last years.

The substantial potential for anti-aging therapy was observed in many natural (Cătană et al. 2018) and chemically synthesized (Vaiserman et al. 2016) substances. Compounds able to mimic the effects of calorie restriction (e.g., rapamycin, metformin, etc.) are thought to be the most promising among them (Madeo et al. 2019). High hope in treating aging-associated chronic disorders also are placed on antioxidants such as quercetin, coenzyme Q10, vitamins A, C and E and melatonin (Wojcik et al. 2010). Other potentially promising anti-aging therapeutics include inductors of autophagy (Nakamura and Yoshimori 2018; Madeo et al. 2018) and senolytics (drugs that selectively target senescent cells) (Li et al. 2019; Sikora et al. 2019). Pharmacological agents targeted to enzymes involved in processes of epigenetic regulation, in particular, inhibitors of histone deacetylases such as suberoylanilide hydroxamic acid (SAHA), valproic acid, sodium butyrate and trichostatin A are one more promising drug class for pro-healthspan and anti-aging intervention (Vaiserman and Pasyukova 2012; Pasyukova and Vaiserman 2017; McIntyre et al. 2019). All compounds mentioned above were found to have the potential to extend life expectancy up to 25–30% in various animal models and some of them have already reached clinical trials for treating age-associated conditions (Vaiserman et al. 2016). Additionally, profound capabilities to combat aging-related disabling conditions and chronic illnesses were shown for many phytobioactive compounds including catechins, curcumin, epigallocatechin gallate (EGCG) and genistein (Martel et al. 2019). Substantial anti-hypertensive and anti-obesity capacities have been also found for certain secondary metabolites derived from seaweeds (Muradian et al. 2015; Seca and Pinto 2018). The safety and efficiency of these compounds were, however, not approved by the FDA by now, so they are not discussed in this chapter.

An important consideration in this context is, however, that most agents having anti-aging potential are obviously multifunctional and targeted at different molecular and cellular pathways underlying aging processes. Furthermore, overall health benefits of these substances have only recently begun to be examined and only limited evidence was found for their capacity to substantially promote human healthspan to date. Research findings from observational and clinical studies aimed at evaluating the efficacy and long-term safety of these drugs are often inconsistent and vary among different investigations. Furthermore, data from some studies indicate that long-time uncontrollable intake of such medications can be unnecessary or even dangerous. In the subsequent sections, research findings in this field will be summarized and discussed.

3 Antioxidants

Long-term consumption of dietary antioxidants is traditionally considered by most healthcare professionals and patients/consumers as a reasonable option to promote human health and wellbeing (Huang 2018). They are also suggested to combat various aging-associated diseases such as atherosclerosis, inflammatory conditions, cardiovascular disease and cancers (Tan et al. 2018). This therapeutic strategy is based on the assumption that excessive production of reactive oxygen species (ROS) and subsequent decrease in vascular bioavailability of nitric oxide (NO) is the common pathogenetic mechanism of the endothelial dysfunction and atherosclerotic process, resulting from diverse cardiovascular risk factors such as hypercholesterolemia, hypertension, metabolic syndrome, type 2 diabetes, and smoking (Münzel et al. 2010). It is commonly believed that dietary antioxidant supplementation may be especially useful in therapy for aging-associated diseases. This is because elderly people are quite susceptible to high oxidative stress levels due to the decreased performance of their endogenous antioxidant systems (Conti et al. 2016).

Life-extending effects of antioxidants were reported in many animal models. These effects were generally accompanied by reduced levels of oxidative stress, elevated activity of antioxidant enzymes, enhanced stress resistance and reproductive activity, and also by changed expression of aging-related genes (Vaiserman et al. 2016). Findings from pre-clinical and clinical studies examining the effects of dietary supplementation with antioxidants such as vitamin C, vitamin E, and also folic acid in combination with vitamin E in human populations have been, however, disappointing. Overall health outcomes of such interventions are often ambiguous or uncertain (Goszcz et al. 2015). Indeed, meta-analyses of observational studies and clinical trials on the topic have indicated that long-term consumption of dietary antioxidants, e.g., β-carotene and vitamins A and E, may even result in adverse health outcomes and in elevated cancer and all-cause mortality rates; these unfavorable outcomes were shown to be more pronounced in well-nourished populations (Bjelakovic et al. 2013, 2014). Such discrepancy between data from animal and clinical studies is now commonly referred to as an “antioxidant paradox” (Biswas 2016). This paradox, consisting in little or no preventive/therapeutic effects of dietary antioxidant supplements despite obvious involvement of oxidative stress in most chronic diseases, can likely be explained by the dual roles of antioxidants in ROS production. Indeed, exogenous antioxidants may act not only as ROS scavengers, but they can also be easily oxidized and act as pro-oxidants thereby promoting damage of biomolecules when present in large concentrations (Milisav et al. 2018). Moreover, since oxidative stress and inflammation coexist in most diseases, the failure of clinical trials with dietary antioxidants can be explained by their incapability to simultaneously target both oxidative stress and inflammation. Indeed, they can block certain pro-oxidative and/or proinflammatory pathways but at the same time reinforce others (Biswas 2016). In addition, increasing evidence indicates that ROS play essential roles as important secondary messengers implicated in various vital processes such as cell survival, apoptosis, proliferation, differentiation and intracellular signaling, and also stress and immune responses (Bardaweel et al. 2018; Milkovic et al. 2019). The considerations above imply that oxidative stress may cause both harms and benefits for human health, depending on particular conditions and circumstances (see Fig. 27.2 for illustration), and targeting ROS-induced diseases by dietary antioxidants is an extraordinarily complex and difficult task (Toledo-Ibelles and Mas-Oliva 2018).

Fig. 27.2
figure 2

Summary of the bifurcated effects that can be induced by ROS. On the one hand, ROS induces the oxidative damage to proteins, DNA and lipids. On the other hand, they also trigger the organism’s adaptive responses including antioxidant and heat shock responses, fatty acid deacylation-reacylation, cell cycle regulation, DNA repair and apoptosis, unfolded protein responses, and autophagy stimulation. On the other hand, they also trigger the organism’s adaptive responses including antioxidant and heat shock responses, cell cycle regulation and apoptosis, unfolded protein responses, and autophagy stimulation. This figure is reproduced from an Open access article by Mao and Franke (2013), which is published under a Creative Commons Attribution License

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In conclusion, dietary supplementation with synthetic antioxidants can likely prevent ROS-induced damage under oxidative stress caused by environmental oxidant exposures or at impaired endogenous oxidative stress responses of an aged individual. The existing evidence however suggests that supplements with synthetic antioxidants often cannot provide appropriate protection against oxidative damage in normal situations and that using antioxidants to prevent aging-related chronic disorders is controversial in the situation of the normal oxidative stress levels. Thus, dietary antioxidant supplementation may be admissible in case of chronic diseases, including aging-associated ones, caused by strongly disturbed balance between oxidative and antioxidative processes and related sustained inflammation such as inflammatory bowel disease, chronic obstructive pulmonary diseases, and also neurodegenerative and cardiovascular disorders (Liu et al. 2018). Therefore, there is a need for accurate determination of the levels of individual’s oxidative stress before prescribing the antioxidant supplements. In addition, development of innovative biotechnological strategies (e.g. nanotechnology-based platforms for targeted antioxidant delivery to specific organs or tissues differing in redox state within the body) may open new horizons for further healthspan-promoting antioxidant therapies (Lushchak et al. 2019).

4 Melatonin

Melatonin is a natural hormone secreted from the pineal gland at night. Aside from the key role in regulating sleep–wake cycle, it demonstrates many vital abilities, including antioxidant, anti-inflammatory, neuroprotective, blood pressure-reducing, pain-modulating, retinal, vascular and anti-tumor activities (Claustrat and Leston 2015; Emet et al. 2016). The role of melatonin in aging-associated processes is clearly evident from observations that various aging-related pathological conditions are related to the loss of melatonin secretion and declining the amplitude of the circadian melatonin rhythm (Hardeland 2012, 2013).

Despite high hopes associated with the use of melatonin, there are yet some concerns about its supplementation. An important point is that it is differently regulated across countries. Indeed, it is regulated in Canada as a natural health product, in the USA as a dietary supplement, and in Australia as a prescription medicine (Dwyer et al. 2018). Therefore, it is available in varied doses and formulations, representing a very heterogeneous group of products whose efficacy and safety are supported by limited data only. Moreover, although melatonin is relatively non-toxic, several moderate side effects have been reported, especially under long-term supplementation at doses much higher than those which are normally produced in the body. These potential side effects include drowsiness, headaches and nausea (Posadzki et al. 2018). Thus, the issues related to the overall safety and potential side effects of melatonin still need to be addressed. This is especially true for older people. Evidence was obtained that melatonin can stay active in elderly people longer than in young subjects and leads to daytime drowsiness. In particular, the 2015 guidelines by the American Academy of Sleep Medicine recommend against the use of melatonin for patients with dementia (Auger et al. 2015).

5 Caloric Restriction Mimetics

Caloric restriction (CR) is regarded now as the most effective and reproducible strategy to slow down aging and increase the healthspan. CR commonly refers to a reduced calorie intake without essential nutrient deficiency (Most et al. 2017). Generally, CR represents feeding a diet containing all essential nutrients, minerals and vitamins but having reduced (by 20–60% compared to ad libitum levels) amounts of calories (Ingram and Roth 2015; López-Lluch and Navas 2016). In experimental studies, CR was shown to be the most effective pro-longevity intervention to date (Liang et al. 2018).

The ability of CR to slow down aging and promote longevity has attracted great scientific attention since the pioneering works of McCay and colleagues conducted as early as the 1930s. In these experiments, it has been demonstrated that rats maintained on a 40% CR had up to 50% longer median and maximal lifespans than rodents fed a standard diet. Afterwards, it has been repeateadly confirmed that CR may slow down aging processes and extend longevity in various species including yeast, worms, insects and rodents (Ingram and Roth 2015; Ingram and de Cabo 2017). Recently, evidence has also been provided that CR may delay the onset of aging-associated pathologies in nonhuman primates such as rhesus monkeys. More specifically, CR slowed down the rate of age-associated muscle loss, reduced body fat levels, improved glucose tolerance and insulin sensitivity, and also lowered incidence of cardiovascular disease, type 2 diabetes and cancer (Colman et al. 2014; Balasubramanian et al. 2017). Furthermore, CR led to a reduced rate of age-related mortality in primates (Colman et al. 2014). Accumulating data also indicate that moderate CR can reduce cancer risk, and cause protective effects against hypertension, type 2 diabetes, obesity, inflammation, and cardiovascular disease in humans. Observational studies and randomized clinical trials have demonstrated that CR in humans caused metabolic and molecular adaptations similar to those found to improve health status and retard the accumulation of age-related molecular damage in various animal models (Most et al. 2017). Generally, the beneficial outcomes of CR have been shown to be mediated by activating pathways that are known to contribute to the regulation of repair, immunity and metabolism, as well as thermoregulation and appetite (Le Couteur et al. 2012). Such advantageous effects of CR likely result from highly regulated processes arising through activation of specific effectors (Mouchiroud et al. 2010). Among the nutrient-sensing pathways implicated in the control of longevity by CR, there are the insulin/insulin-like growth factor signaling, adenosine monophosphate (AMP)-activated protein kinase (AMPK) and mTOR pathways, and also sirtuins, particularly SIRT1. These pathways are well known to be key regulators of cell growth, mitochondrial function, autophagy and proliferation, and they are also known to be regulated by interaction with one another.

Despite the fact that CR may clearly postpone the development of most aging-associated disorders, it is a subject of debate so far whether it could extend the human health- and lifespan. In experimental studies, CR did not always lead to uniquely positive effects with respect to longevity (Sohal and Forster 2014). Several authors assume that control animals that fed on basal ad libitum diet are often overweight and are at risk for associated health problems. Thereby, they would seem not to be suitable for investigating longevity (Sohal and Forster 2014). Nonetheless, even despite these obvious challenges and limitations, the concept of CR continues to be one of the major paradigms in modern biogerontology (Ingram et al. 2006; Ingram and Roth 2015).

From a translational perspective, an important point is that long-term (usually more than 3 months) CR is necessary to induce pro-healthspan effects in human beings (Ingram and Roth 2015; López-Lluch and Navas 2016). It seems obviously problematic, making such interventions difficult to apply for most modern people. Doubts about the applicability of the CR-based treatments have driven a rising interest in elaboration of alternative treatment strategies that might provide pro-healthspan CR benefits without severe restriction in food intake. Currently, several compounds are developed for use in these therapies. Such substances are commonly referred to as CR mimetics (Lushchak and Gospodaryov 2016). Basic characteristic properties of CR-mimicking agents are as follows: (1) inducing the physiological, hormonal and metabolic effects which are similar to those induced by CR; (2) activating the stress response pathways like CR; (3) extending the lifespan and delaying the onset and/or reducing the incidence of age-related disorders (Ingram et al. 2006). The most promising pharmacological agents modulating these pathways by mimicking CR effects and also challenges related to their application are reviewed and discussed in the subsections below.

6 Metformin

Currently, metformin (dimethyl-biguanide) is considered to be a first-line drug in treating type 2 diabetes (Sanchez-Rangel and Inzucchi 2017). It is the derivative of galegine, a hypoglycemic substance from the plant French lilac, Galega officinalis, which was widely used in herbal medicine in medieval Europe (Bailey 2017). After the long-term cardiovascular benefits of this glucose-lowering medicine were identified in 1998 by the UK Prospective Diabetes Study (Turner 1998), metformin was implemented as an initial therapy to manage hyperglycemia in type 2 diabetes. Physiologically, the effects of this antidiabetic biguanide may be explained by suppressing hepatic gluconeogenesis without inducing weight gain, enhancing insulin secretion, and posing a hypoglycemia risk (Madiraju et al. 2014). The precise molecular mechanisms underlying these effects remain largely unknown, but modulating the AMPK pathway which maintains the cellular energy balance by changing ATP production appears to play a major role in metformin action (Rena et al. 2017). These effects are also likely related to (AMPK)-independent mechanisms, such as inhibition of mitochondrial respiration and lysosome-related mechanisms. Due to these mechanisms, metformin inhibits the liver mitochondrial respiratory chain, resulting in activation of AMPK, improving insulin sensitivity (due to effects on fat metabolism) and reducing the mRNA levels of gluconeogenic enzymes (Rena et al. 2017).

Since metformin decreases hepatic glucose production, it may also act as a CR mimetic (Viollet et al. 2012). Treatment with metformin was shown to cause life extension in various animal models including worms, flies and rodents (Piskovatska et al. 2019a, b). Evidence for pro-health effects of metformin, including reduced incidence of neurodegenerative disease and cancer, has also been provided in several human studies (Soukas et al. 2019). Significant improvement in body mass index, total cholesterol, low-density lipoprotein cholesterol, and non-high density lipoprotein cholesterol was, in particular, found in the metformin-treated children with metabolic syndrome (Luong et al. 2015). Anti-cancer effects of metformin have also been observed in both diabetic and non-diabetic persons (Coperchini et al. 2015).

It is, however, unclear to what extent these pro-healthspan effects of metformin may be mediated by activating AMPK. Over the past decade, a simple view that metformin may improve glycemic status by acting on the liver through the activation of AMPK, has been moved to a much more complex view reflecting the multiple modes of action of this drug (Rena et al. 2017). Indeed, evidence is obtained that AMPK-independent pathways may also be implicated in its effects, either beneficial or harmful (Zheng et al. 2015). These pathways include inhibition of mitochondrial shuttles, suppression of glucagon signaling, induction of mitochondrial stress and autophagy, attenuation of inflammasome activation and reduction of terminal endoplasmic reticulum stress (Hur and Lee 2015). Remarkably, substantial similarity between alterations in gene expression profiles induced by both metformin and CR was shown by microarray analysis (Dhahbi et al. 2005). Moreover, importantly, some observations suggest that beneficial effects of metformin might be indirectly mediated by the effects on intestinal microbiota (MacNeil et al. 2019). Recent evidence indicates that metformin may modulate the gut microbiome via promoting the expansion of beneficial bacteria and counteracting the growth of harmful bacterial species (Prattichizzo et al. 2018). It is hypothesized that such an action may positively shift the balance between pro- and anti-inflammatory mediators, thereby improving glycemic control and promoting healthspan.

A recent meta-analysis indicated that therapy with metformin may exert beneficial effects on all-cause mortality and incidence of aging-related diseases, such as cardiovascular disease and cancer, in type 2 diabetes patients compared to diabetics receiving other therapies, and also to non-diabetic populations (Campbell et al. 2017). These findings, collectively, suggest that metformin can act as a geroprotective agent. To verify this assumption, a placebo controlled, multi-center study named TAME (Targeting Aging with MEtformin) in ~3000 elderly aged 65–79 has been recently designed (Barzilai et al. 2016). The aim of this study was to investigate whether metformin can be repurposed to target aging per se and whether it is able to reduce the risk for various geriatric syndromes and aging-related diseases as well as the functional health status. An important point is that this research has been developed in consultation with the FDA to obtain a novel FDA indication to specifically target aging. It is believed that such an indication would allow regulatory authorities to approve designs aimed at the development of next-generation drugs to target aging and extend human healthspan.

In implementing a therapy with metformin in aged healthy persons, however, certain potential side effects related to such a treatment modality should obviously be taken into account. Indeed, reasonable concerns exist among many medical professionals regarding the adverse effects of metformin such as gastrointestinal disorders and lactic acidosis (Pryor and Cabreiro 2015). It has also been found to induce hyperhomocysteinemia, deficiency of vitamin B12 and vascular complications in type 2 diabetes patients (Glossmann and Lutz 2019), and also cognitive dysfunction (Porter et al. 2019). These side effects of metformin should be, of course, thoroughly evaluated before such a therapy will be put into practice.

7 Rapamycin

Rapamycin (sirolimus) is a natural macrocyclic lactone fermentation compound produced by the bacteria Streptomyces hygroscopicus. Initially, rapamycin was developed as an antifungal agent but subsequently it has been shown to have strong regulatory effects on basic biological processes such as cellular growth and proliferation and also on inflammatory pathways due to its inhibitory action on the mTOR pathway (Lamming et al. 2013; Lushchak et al. 2017). Since rapamycin has been found to inhibit immune responses, it was subsequently applied in immunosuppressive therapy in order to prevent graft rejection and treat autoimmune diseases (Ingle et al. 2000). Presently, rapamycin and its analogs (rapalogs), such as everolimus and temsirolimus, are assumed to be among the most promising anti-aging ingredients (Blagosklonny 2007). In different rodent models, rapamycin administration was repeatedly found to be able to delay aging-associated pathological conditions, including accumulation of the sub-cellular myocardium changes, endometrial hyperplasia, tendon stiffening, liver degeneration, and decline in physical activity (Wilkinson et al. 2012). It is also proved to be efficient in combating various aging-related pathologies including retinopathy, atherosclerosis, cardiac hypertrophy, cognitive decline, neurodegenerative disorders, and loss of stem cell functioning (Blagosklonny 2017).

However, even although rapamycin was approved by the FDA and is now being widely used worldwide, many clinicians believe that its application may result in serious metabolic impairments, including type 2 diabetes and, therefore, this medication cannot be safely used as an anti-aging drug. This concern is primarily due to the fact that long-time intake of rapamycin can be associated with enhanced risk of developing insulin resistance (Blagosklonny 2012). Such an effect of rapamycin, however, may be more complicated and ambiguous than it seems to be at first sight. Indeed, rapamycin may induce, in certain circumstances, a complex conglomerate of conditions related to (dys)regulation of insulin signalling, including insulin sensitivity, insulin resistance and also glucose intolerance without insulin resistance (Blagosklonny 2019a, b). Remarkably, these effects are similar to those seen in very low caloric diets or fasting. An important point is that both these dietary regimes are shown to improve insulin sensitivity and reverse type 2 diabetes, but they also may lead to a specific kind of glucose intolerance currently referred to as starvation-induced pseudo-diabetes. The concept of starvation-induced pseudo-diabetes is related to the idea that insulin resistance is an adaptive mechanism which can become maladaptive under particular conditions. From these assumptions, it is suggested that starvation/fasting may result in decreased insulin levels and cause insulin resistance originating as a compensatory response designed to saving glucose for the brain (Watve and Yajnik 2007; Tsatsoulis et al. 2013). Moreover, glucose utilization by the brain is decreased during prolonged starvation since the brain begins to utilize ketone bodies as the major fuel. Remarkably, there is evidence that the insulin-resistant state can be associated with life extension in animal models. For instance, insulin receptor substrate 1 null mice (Selman et al. 2008) and Klotho overexpressing mice (Kurosu et al. 2005) were shown to live longer than controls even though they exhibit insulin resistance. Recently, Blagosklonny (2019a,b) introduced the term benevolent pseudo-diabetes, or benevolent glucose intolerance to refer to this phenomenon. Indeed, there is no indication until now that starvation-induced pseudo-diabetes is detrimental. Although pseudo-diabetes shares several hallmarks with “typical” diabetes, it is really not true diabetes and does not lead to the most common diabetic complications. By contrast, it was associated with improved health and life extension in several studies. To overcome concerns related to inducing hyperglycemia through rapamycin treatment, Blagosklonny (2019a) proposed to use a combination of rapamycin and an anti-diabetic drug such as metformin. Indeed, some experimental evidence indicates that rapamycin-induced hyperglycemia can be attenuated by simultaneous treatment with metformin (Weiss et al. 2018), and such treatment may be well tolerated by patients (Sehdev et al. 2018). So, such a therapeutic strategy may likely be useful in further healthspan-promoting interventions.

8 Aspirin

Aspirin, also known as acetylsalicylic acid, is a most commonly used nonsteroidal anti-inflammatory drug. Historically, this synthetic drug was developed based on an extract from the bark of the white willow tree, Salix alba (Montinari et al. 2019). Its active ingredient, salicin, is converted to salicylic acid in the body, thus resulting in many therapeutic benefits. Due to these benefits, the bark of the willow tree has been used medicinally since ancient times. Currently, aspirin is one of the most widely used non-prescription drugs. Its mechanism of action is based on inhibiting the activity of a specific enzyme, cyclooxygenase (COX) and preventing the formation and release of prostaglandins and precluding inflammation (Botting 2010). However, by inhibiting this enzyme involved in the prostaglandin synthesis, aspirin and aspirin-like drugs also prevent the production of physiologically important prostaglandins protecting the stomach mucosa from damage by hydrochloric acid and maintaining kidney function and aggregate platelets when required (Vane and Botting 2003). Moreover, it has been discovered that there exist two different isoforms of the COX enzyme. The constitutive isoform, COX-1, was shown to support vital homeostatic functions, while inflammatory mediators activate the inducible isoform, COX-2, and its products cause symptoms of inflammatory states such as osteoarthritis and rheumatoid arthritis (Vane and Botting 2003). Presently, aside from inflammatory conditions, aspirin is widely applied to treat pain, fever, and platelet aggregation, as well as to prevent cardiovascular diseases and cancer (Thun et al. 2012). Since aspirin may affect ROS production, cytokine responses and block glycooxidation reactions, which are all regarded as common hallmarks of aging, it was proposed to be a promising anti-aging agent (Phillips and Leeuwenburgh 2004).

Evidence was obtained that aspirin is able to reduce age-associated functional declines and extend longevity in different animal models (Danilov et al. 2015). In humans, aspirin is widely used due to its established antithrombotic action. It can inhibit the platelet function by irreversibly inhibiting the COX activity; therefore, it has been mainly used until recently for primary and secondary prevention of arterial antithrombotic events (Mekaj et al. 2015). Furthermore, this medication is commonly indicated for primary and secondary prevention as well as for the treatment of various diseases. Among them, there are cardiovascular diseases such as acute coronary syndrome, peripheral artery disease, myocardial infarction, acute ischemic stroke, and also transient ischemic attack. In epidemiological and clinical studies, evidence was also obtained that aspirin may reduce cancer incidence and mortality by influencing both COX and non-COX pathways (Ma et al. 2017). Several studies also indicated that aspirin, among other non-steroidal anti-inflammatory drugs, may reduce the risk for age-related neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases, although findings from these studies are rather inconclusive (Auriel et al. 2014).

Although aspirin is currently among the medications most widely used by middle-aged and older adults to prevent heart attacks and stroke, its regular use is largely limited by serious adverse effects (Huang et al. 2011). When tested in clinical trials for primary prevention of predominantly low risk individuals, aspirin was demonstrated to decrease the rate of cardiovascular events but with an almost equivalent increase in the risk of gastrointestinal bleeding (Nansseu and Noubiap 2015; Gelbenegger et al. 2019). Consequently, expert recommendations for aspirin use in primary prevention of cardiovascular events differ substantially, reflecting uncertainty of the benefit/risk ratio in the choice of treatment strategies for at-risk patients.

9 Statins

Statins are a drug class able to significantly reduce levels of cholesterol and triglycerides in the bloodstream. Their lipid-lowering effect is attributed to inhibiting the critical step of cholesterol synthesis in the liver via the mevalonate pathway. An important point is that, as the mevalonate pathway also affects the inflammatory responses, as well as endothelial function and coagulation, the effects of statins can reach well beyond their cholesterol-lowering capabilities (Pinal-Fernandez et al. 2018). Owing to these pleiotropic effects known to play an important role in aging-related processes, statins have attracted a lot of interest in anti-aging medicine recently. In the U.S., a highly significant negative association with death was demonstrated for statin users, and the mean age at death was two years higher among statin users than among nonstatin users, even despite the statin users being at a higher risk of death (Mehta et al. 2006). Treatment with statins caused significantly increased survival rate among the very old subjects (aged 85–90 years). Remarkably, the extension of life in these individuals was independent of the cholesterol level (Jacobs et al. 2013). More recently, preserved resilience and survival were found among the statin users in the community-dwelling male octogenarians (Luotola et al. 2019), and also in debilitated nursing home residents (Schlesinger et al. 2019). In a retrospective cohort study, statin use was not associated with a reduction in atherosclerotic cardiovascular disease or in all-cause mortality in participants older than 74 years without type 2 diabetes (Ramos et al. 2018). In the presence of type 2 diabetes, however, treatment with statins was associated with substantial reduction in the incidence of atherosclerotic cardiovascular disease and in all-cause mortality. This effect was diminished after the age of 85 years and disappeared in nonagenarians.

The potential adverse effects of statin therapy are also described. Along with unfavorable effects on liver and muscle recognized soon after introducing statins in the 1980s, these effects include risks of new-onset diabetes, cognitive impairments and hemorrhagic stroke associated with achieving very low levels of low-density lipoprotein cholesterol (Adhyaru and Jacobson 2018; Newman et al. 2019). Recognition of these side effects of statins and the increased media attention to potential adverse events associated with their use cause concerns about initiating such a therapy or its discontinuation by many patients. However, recent large-scale studies on this issue indicated that the frequency of these adverse effects is extremely low, so benefits of statin therapy in patients for whom statin treatment is recommended by current guidelines, far outweigh any perceived or real risks (Adhyaru and Jacobson 2018; Pinal-Fernandez et al. 2018).

One of the most debatable issues in this context is whether statins can be used in the elderly. Indeed, while for most patients, the benefits of statin therapy outweigh its possible adverse effects, the impact of statins on musculoskeletal ability, cognitive function, and independence need to be heavily weighed before prescribing such therapy in individuals over 75 years of age (Leya and Stone 2017). It seems especially important considering that levels of serum cholesterol tend to increase in adult age, but subsequently decrease in the very elderly. Therefore, the use of cholesterol-lowering agents like statins in old age seems extremely controversial and the benefit/risk ratio have to be weighed carefully before prescribing statins, especially to patients over 75 (Leya and Stone 2017; see also Fig. 27.3 for schematic illustration).

Fig. 27.3
figure 3

Pros and cons for the statin use

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10 Conclusions

The aging process is commonly believed to be an inevitable part of the human life cycle. According to many experts, however, this opinion appears rather questionable (Mitteldorf and Fahy 2018). A large body of research evidence indicates that aging is neither inevitable nor universal; indeed, germ lines and several organisms (e.g. Hydra) do not exhibit any noticeable senescent decline (Flatt and Partridge 2018). Therefore, aging is assumed to be “druggable” like other pathological conditions (Flatt and Partridge 2018). One widely-discussed issue among the general public, physicians and governmental regulators regarding intervention in the aging process is the concern that the rise in human life expectancy might lead to a rise in the proportion of older people in general populations across countries and, consequently, to a higher prevalence of aging-associated chronic conditions. It could become an overwhelming economic and social burden for the future generations. These concerns, however, seem largely unfounded. Indeed, in various animal models, pharmacological lifespan extension was shown to be accompanied by decreased or delayed morbidity, including a reduced incidence of neurodegenerative and cardiovascular diseases, as well as cancer (Fontana et al. 2010). Moreover, observational findings obtained from human populations are mostly consistent with these findings from animal models. For example, centenarians living in so-called Blue Zones (regions where people live much longer than average) were found to remain free from disabilities and chronic diseases until a very old age (Willcox et al. 2008). Based on this, we can assume that properly matched pharmacological interventions in the aging process would rather lead to healthspan extension due to delaying the onset of aging-associated chronic pathologies and to compressing aging-related morbidity to only the very last years of the life course. Another potential issue is that certain anti-aging drugs may exert beneficial effects on some aging-related pathways but simultaneously adversely impact others. In order to overcome this obstacle, the application of drug cocktails to contemporaneously affect multiple pathways was proposed (Ingram and Roth 2015). One example of such a treatment approach is the use of metformin to overcome the rapamycin-induced glucose dysmetabolism (Mendelsohn and Larrick 2012). Another example is the combined therapy of rapamycin with statins, proposed to mitigate the rapamycin-induced dyslipidemia (Blagosklonny 2017). Such a combined approach can likely provide a more balanced and secure treatment mode than if one drug alone is used, especially in healthy individuals. Evidence for efficiency of such a cocktail-based approach was recently obtained in a small-size Thymus Regeneration, Immunorestoration and Insulin Mitigation (TRIIM) trial conducted by Fahy et al. (2019). In this trial, the cocktail consisting of the growth hormone and two anti-diabetic drugs, dehydroepiandrosterone and metformin, was applied. Anti-diabetic medications were used in this study since it is known that treatment with growth hormone may promote diabetes. In this trial, improved risk indices for various age-related diseases and a mean epigenetic age approximately 1.5 years less than baseline have been observed after one year of treatment. The immune systems of the study participants also demonstrated signs of rejuvenation.

Conducting clinical trials aimed at investigating the healthspan-promoting potential of conventionally used drugs certainly represents a very difficult task. This difficulty is, in particular, related to the fact that elderly patients are typically multimorbid and get multiple drugs. According to current estimates, more than one third of elderly patients simultaneously use five or more prescription drugs, often along with the intake of one or more over-the-counter drugs or dietary supplements (Maher et al. 2014). Therefore, the results of clinical trials conducted with geriatric patients can be significantly confounded by certain drug-drug interactions (Shenoy and Harugeri 2015). One more important limitation of randomized controlled trials in geriatric patients is considering defined age and/or concomitant disease as exclusion criteria. It makes it difficult to precisely estimate the entire spectrum of anti-aging and healthspan-promoting effects of the investigated medications (Zulman et al. 2011). Furthermore, since many drugs have a “therapeutic window” of effect, which means that either too little or too much (and also too early or too late) intervention may prevent the optimal response, the proper dosing and life-course timing of healthspan-promoting drugs have to be thoroughly determined prior to their application (Burd et al. 2016; Piskovatska et al. 2019a, b). An important question is also whether health status could depend differently on the mode of intervention, e.g., cholesterol-reducing effects of statins, glucose-lowering effects of metformin, anti-inflammatory effects of aspirin, autophagy-inducing effects of spermidine, etc.

The important consideration in designing clinical trials for healthspan-promoting interventions is also the choice of outcome measure (Fleming and Powers 2012). Indeed, clinical evidence for effectiveness of such interventions is typically based on the data regarding the prevention or treatment of particular aging-related disorders, but not on the early markers of age-related functional declines and aging rate per se. This is an important obstacle in terms of a translational perspective. Indeed, as stated in the WHO World Report on Ageing and Health (2015), “healthy ageing is more than just the absence of disease; the maintenance of functional ability has the highest importance.” Thus, the conclusion about the efficiency of healthspan-promoting interventions cannot be done only based on disease prevention/treatment. In addition, the success of such therapy obviously depends on the health status of the intervention group. Indeed, the success of such therapy in a group of sick people will not necessarily mean that it will be just as successful when used in healthy subjects. The lack of reliably measurable biomarkers to evaluate the rate of human aging and effectiveness of anti-aging interventions remains an important challenge in this field (Moskalev et al. 2016). Therefore, the development of innovative algorithms to accurately determine the biological age of people in order to evaluate their health status and to access the efficiency of healthspan-promoting interventions is of paramount importance in biogerontological research.

In conclusion, since processes implicated in aging are extraordinarily complex and intertwined, the healthspan-promoting effects of anti-aging pharmacological interventions are often unsatisfactory and greatly limited by their side effects. So, implementation of such treatment modalities in routine clinical practice is apparently a long-term process that will require numerous translational steps to address ongoing and future challenges in the field. After overcoming these obstacles, however, implementing such therapeutic approaches can undoubtedly provide innovative strategies for human healthspan extension.