Geroscience: life to years not years to life

Over the past decades, the compression of the morbidity was a basic strategy in gerontology. This strategy is aimed at limiting morbidity to a short time period near the end of life, thereby reducing the burden of diseases and disabilities through delay in the age at onset of the most common aging-related pathological conditions [16]. A few years ago, a new direction in geriatric medicine, geroscience, began to develop. This interdisciplinary field of research is aimed at understanding the mechanistic links between aging and aging-associated diseases [17, 18] and centered primarily on extension of healthspan [19]. According to the “geroscience hypothesis”, aging could be manipulated in such a way that will in parallel allow delay the onset of all age-associated chronic disorders, because these pathologies share the same primary underlying risk factor (age) [13, 17].

Healthspan extension is a central component of activities aimed at achievement of ‘optimal longevity’, a condition defined as ‘living long, but with good health and quality of life’ [16] including improved productivity, functioning and independence. Currently, the research attempted to enhance healthspan are focused primarily on slowing the biological processes underlying aging such as dysfunctions of mitochondria, impaired proteostasis and stem cell function and maintenance, deregulated sensing of cell energy status and growth pathways, cellular senescence, age-related decrease in stress resistance, as well as oxidative and inflammatory stress [20–22]. These processes interact, influencing each other in order to maintain the normal pathways of cellular signaling and to support organismal homeostasis. The compensatory mechanisms mediating these processes, however, became exhausted when reaching a certain age and various aging aspects are manifested, enhancing as a consequence the risk of functional declines and progression of age-associated chronic pathologies [23].

Anti-aging medicine

The research field targeted at providing therapeutic options to combat the aging-related functional declines and chronic disorders is generally referred to as ‘anti-aging medicine’. This area of investigation, emerging since the beginning of 1990s, has become a hotly discussed topic in the past two decades [24, 25]. Its main purpose is to promote healthspan and lifespan by specific dietary and exercise regimes, as well as by biomedical interventions aimed at delaying or slowing the aging process [26, 27].

Aging is traditionally regarded as ‘natural’ and consequently unpreventable process. However, in the opinion of many field experts, the idea that aging is inevitable part of human nature is rather questionable [28]. Indeed, most present-day evolutionary theories postulate that aging has arisen as a by-product of fundamental evolutionary processes and does not have any specific function [29]. If aging is in fact not an inadmissible component of life, then it might be manipulated like other processes that are commonly believed to be pathological or unnatural. The basic supposition underlying anti-aging research is that age-associated senescence may be regarded as a complex of pathophysiological processes that could be prevented, delayed or even reversed [30]. Currently, biotechnological innovations that potentially may slow down or postpone processes involved in aging are widely implemented in anti-aging medicine [3]. Achievements in this field are to a great extent attributed to an increasingly widespread implementation of ‘omics’ platforms such as genomics, transcriptomics, proteomics and metabolomics [31].

Through the broad implementation of such technologies, a deeper understanding was gained of the fundamental molecular and cellular processes underlying aging, including genomic instability, epigenetic deregulation, loss of proteostasis, mitochondrial dysfunction, cellular senescence, exhaustion of stem cells, inflammation, telomere shortening, autophagy, impaired stress resistance and deregulated nutrient signaling [32–34]. Based on this new knowledge, novel therapeutic strategies to counteract age-associated functional declines and pathological conditions are being developed. In the long run, most promising among them are apparently stem cell- and gene therapy-based approaches. Presently, however, due to insufficient knowledge regarding the potential side effects of these technologies, including cancer, uncertainties and concerns still prevail about their safety among the general public and medical professionals. Therefore, the use of more traditional pharmacological interventions can be considered as a reasonable alternative now [35].

Anti-aging pharmacology: opportunities and challenges

The further elaboration of pharmaceuticals (both supplements and clinically approved drugs) specifically targeted at age-related pathologies is one of the most rapidly developing fields in modern biogerontology. Over the last 20 years, an exponential rise of research dedicated to investigating substances with potential for use in geriatric practice is observed [36].

In pharmacological research, the first step in the process of drug development is search for druggable molecular targets [37]. In this context, experimental approaches based on using gain- or loss-of-function phenotypes are very helpful to determine gene targets substantially implicated in aging processes [33]. In recent years, this approach has been used to identify many genetic pathways strongly linked to aging and longevity [33, 38]. Nowadays, all these pathways are considered to be promising targets for drugs and several pharmaceuticals targeting them are already under intensive investigation and development.

Identification of processes underlying aging and further development of interventions addressing these processes is apparently a challenging task considering the extreme complexity of aging-related processes. Substantial progress has been, however, achieved during recent years in this field of investigation. Some classes of chemically synthesized compounds and nutraceuticals were identified as having potential for anti-aging intervention [4, 35]. Several substances capable of mimicking the effects of calorie restriction, such as rapamycin, resveratrol and metformin, are thought to be among the most promising in this respect now [39] In addition, high hopes are placed by some authors on antioxidants (coenzyme Q10, quercetin, melatonin, vitamins A, C and E, etc.) [40], inductors of autophagy such as, e.g., spermidine [41], agents that can selectively target and remove senescent cells (senolytics) [42], phytochemicals, such as epigallocatechin gallate (EGCG), catechins, genistein, curcumin, etc. [43], and also several other natural and synthesized compounds. All these substances have been shown to be able to extend lifespan up to 25–30% in different animal models [35]. Over the last years, biotechnological applications are widely used in anti-aging pharmacology. For instance, nanotechnology-based drug delivery systems were recently proposed as a novel promising approach for Alzheimer’s and Parkinson’s diseases treatment [44]. Small size and thus ability to penetrate the blood–brain barrier is the major advantage on these systems. Medications targeted to enzymes participating in processes of epigenetic regulation of gene expression, for example, inhibitors of histone deacetylases such as suberoylanilide hydroxamic acid, trichostatin A and sodium butyrate are another promising drug class for anti-aging intervention [45]. An overview of the most common anti-aging drugs is given in Table 1. Only agents that have reached clinical trials for treating various age-associated clinical conditions are included in the table. The most comprehensive to date overview of the current state-of-the-art in the field of anti-aging pharmacology is provided in recent paper by Vaiserman et al. [35].

An important point is, however, that most substances with potential anti-aging properties are apparently multifunctional and targeted at various molecular pathways that mediate aging. Furthermore, there is only limited evidence to demonstrate overall health benefits of using such substances so far. Findings from epidemiological studies reporting the long-term health impacts of these agents are rather inconsistent. Moreover, evidence from several studies indicates that uncontrolled consumption of some medications considered as potential anti-aging drugs may be useless or even detrimental.

For example, long-term intake of free radical-scavenging antioxidants is considered by most medical professionals as quite reasonable option to promote health and wellbeing, and also to prevent various aging-related conditions such as atherosclerosis, inflammatory disorders, CVD and cancer [51]. The health outcomes of these interventions, however, are still under debates. Doubts on this matter are strengthened by the results obtained in a series of meta-analyses of randomized controlled trials and observational studies by Bjelakovic and co-authors. Based on these meta-analyses, the authors concluded that long-term intake of dietary antioxidants, such as beta-carotene and vitamins A and E, can be associated with unfavorable health outcomes and with increased cancer and all-cause mortality, especially in well-nourished populations [52, 53]. One more example of potential risk of using compounds with anti-aging properties, such as e.g. calorie restriction mimetics, is that they might induce insulin resistance. Such side effects were observed, in particular, in patients treated with rapamycin [54]. Treatment with rapamycin, among other mechanistic Target of Rapamycin (mTOR) inhibitors, was associated with a 13–50% higher incidence of hyperglycemia and development of T2D if applied as anticancer therapies [55]. Similarly, insulin resistance-inducing effects were also reported for statins. The risk for development of T2D was found to be increased by 9–12% in two meta-analyses of statin trials and by 18–99% in five population-based studies [56].

Another reasonable approach in anti-aging pharmacology is evaluation of the geroprotective potential of medications already approved by the US Food and Drug Administration (FDA) and other regulatory authorities for treating various pathological conditions related to aging. Among them, metformin, statins, beta-blockers, thiazolidinediones, newer generation β-adrenergic receptor inhibitors, renin-angiotensin-aldosterone system inhibitors, as well as anti-inflammatory medications appear to be the most promising drug candidates in this respect [16]. The safety of these drugs has been confirmed in a number of clinical trials. This is also compelling evidence that they may improve health, well-being and physiological functioning in elderly patients suffering from chronic pathologies [57]. One problem is that these substances are not used currently for treating age-related pathological conditions in the absence of clinical manifestations of particular illness. There are, however, good reasons to suggest that these agents could theoretically be redirected to preventing or treating other syndromes or conditions commonly associated with aging.

Longevity dividend

Despite an extraordinary rapid technological progress in pharmacology, there are few new preparations in the development pipeline now. Thereby, drugs generated on the basis of new knowledge gained from biogerontological research that can delay or prevent most age-associated disorders would apparently become “blockbusters” of modern pharmaceutical industry and market [58]. That follows the idea that the extension of the healthy life expectancy by slowing aging process is the most efficient way to combat aging-related chronic illnesses and disabling conditions representing serious medical, social and economic issue in modern societies. This idea is referred to as the “longevity dividend” in the contemporary literature [59].

Discovery and development of anti-aging drugs could likely provide an opportunity for revitalization of the drug development pipeline [58]. Indeed, if it would be possible to slow down the aging process per se, then that would allow delay or prevent most aging-related disorders rather than combating them one by one, which is the conventional approach in the present-day disease-based paradigm of drug development. Moreover, population life expectancy might be only insignificantly affected by preventing only certain pathological conditions. This is due to the fact that other disorders will, due to comorbidity, greatly devalue the positive effects achieved by prevention of the targeted disease. Therefore, simultaneous delaying the clinical manifestations of all aging-associated disorders by inhibiting fundamental aging mechanisms may be much more effective than prevention of particular chronic diseases [16, 57]. It can be also assumed that not only considerable health advantages but also substantially larger socio-economic benefits may be achieved from such approach relative to the conventional approach in present-day public health practice targeted to preventing certain pathological conditions only [60]. Goldman et al. have estimated the economic advantages from enhancing healthspan through slowing down aging process in the US at about 7 trillion dollars over the next 50 years [61].

Prospect debate: should aging be recognized as a disease?

Until recently, substances with potent anti-aging properties were not considered by US FDA and other regulatory agencies as suitable candidate drugs for clinical trials, because they did not recognize aging as a clinical condition. However, it has become increasingly apparent now that such opinion is rather contradictory. Indeed, it’s obvious that aging is generally accompanied by health issues typically associated with clinical conditions such as loss of muscle mass (sarcopenia), osteoporosis, atherosclerosis, hypertension, strokes, heart attacks and atrophy of brain tissues resulting in dementia. Clinically, all of these conditions are recognized as diseases and require specific therapeutic interventions. Therefore, an intense debate has emerged now in both academic and policy making circles on whether or not aging can be classified as a disease [62, 63]. Perhaps as a consequence of this discussion, the FDA’s position on that occasion has become a lot less rigorous in recent years.

AV conceived the idea for the manuscript and produced the first draft. OL was involved in creating the table, an also in critical review and rewriting of subsequent drafts. Both authors read and approved the final manuscript.