Send Orders for Reprints to [email protected] 149 Current Aging Science, 2018, 11, 149-154 REVIEW ARTICLE ISSN: 1874-6098 eISSN: 1874-6128 Four Principles Regarding an Effective Treatment of Aging BENTHAM SCIENCE Marios Kyriazis* National Gerontology Centre, Larnaca 6021, Cyprus Abstract: The question whether aging is a disease or not, has been asked by many professionals who are involved in the study of age-related degeneration. However, not only an agreement on this remains elusive, but also effective clinical treatments against human aging have not been forthcom- ing. In this Opinion paper I suggest that the complexity involved in aging is such that we need to remodel our thinking to involve a much more ‘systems-oriented’ approach. I explore four main A R T I C L E H I S T O R Y principles which should be employed by those who are working on finding treatments against age- related degeneration. First, I discuss the problems encountered in translating laboratory research into effective therapies for humans. Second, I propose that a ‘systems-thinking’ method needs to be Received: May 30, 2018 Revised: September 07, 2018 more extensively employed, instead of relying exclusively on the current reductionist one. Third, it Accepted: October 16, 2018 is submitted that we must learn from the history of life-extension research, and not blindly follow contemporary paradigms, which may lead us into yet more ‘dead ends’ with regards to therapies. DOI: 10.2174/1874609811666181025170059 Finally, I suggest that, we may need to employ certain universal notions and use these in order to gain insights into the mechanics of a possible therapy against age-related degeneration. Examples may be the principle of hormesis, those of degeneracy, exaptation, and others from cybernetic or systems science domains. By using this four-pronged approach we liberate our thinking from the shackles of existing common mistakes and fallacies, and we open the way for a fresh approach that may lead us towards entirely new paradigms for providing clinically effective therapies against age- related degeneration. Keywords: Reductionism, systems thinking, translational research, age-related degeneration, life extension, hormesis. 1. INTRODUCTION With regards to aging, the difficulties in translating research performed on animals to effective clinical treatments for It is important to clarify at the outset that the paper does humans are notorious [3-5]. not only refer to treatments for common, established chronic degenerative clinical conditions (for instance Alzheimer’s We are witnessing an unwarranted dependence on study- disease, Parkinson’s disease or cataract), but it also refers to ing simplistic models of aging, and examining issues relating therapies or treatments, preventative or curative, that may be merely to a ‘bench to bedside’ principle. But in addition to directed at the heart of the aging process itself (such as se- this, there are other stages of the translational process that nolytics, genetic therapies, rejuvenation biotechnologies, or need to be overcome. The following is an outline of a pro- other approaches) [1] which could lower the risk of mortality gressive model of the translation process [6]: as a function of age. In clinical terms, aging is defined as Stage T0 – Prior to conducting the actual research there is ‘time-related dysfunction’, and the overall ideal aim is to a need to identify and describe the subject and potential of postpone this dysfunction indefinitely [2]. With this in mind, this basic research. the paper will explore four main principles which should be considered by those involved in finding treatments for such Stage T1 –This stage aims to bridge the gap between age-related degeneration. The aim is not to elaborate on ex- basic research in the laboratory and possible health applica- isting or emerging approaches to treat age-related degenera- tions. Strictly, this model refers simply to the suitability of a tion, but to ‘zoom out’ of current thinking and examine new treatment in general terms. perspectives which may be useful in this respect. Stage T2- At this next stage it is necessary to evaluate the clinical usefulness (if any) of the therapeutic application. 2. TRANSLATING LABORATORY FINDINGS INTO There is a need to establish if this particular pharmaceutical EFFECTIVE THERAPIES FOR HUMAN AGING product or therapeutic procedure achieves better results than Despite a large amount of laboratory research, effective other common existing therapies in clinical practice. therapies against aging at a clinical level remain elusive. Stage T3 – If there is clinical usefulness, then it must be assessed within a wider, community-based practice. The therapy must be integrated into other existing therapies and *Address correspondence to this author at the National Gerontology Centre, 6021 Larnaca, Cyprus; Tel 00357 97606424; E-mail: [email protected] Current Aging Science 1874-6128/18 $58.00+.00 © 2018 Bentham Science Publishers 150 Current Aging Science, 2018, Vol. 11, No. 3 Marios Kyriazis we must ensure that it reaches the actual patient groups that the number of academics and researchers who think in which may benefit from the therapy in question. terms of ‘magnification’ (systems thinking) instead of ‘miniaturization’ (reductionism) is growing progressively Stage T4- There must be an assessment to establish [16]. In systems thinking we take into account the whole of whether the overall health impact of the particular applica- tion or therapy at a population level is indeed positive. Any the subject in question, and consider the impact of the envi- ronment on this subject. The problem in question is magni- putative improvement must be shown to be measurable and fied, as if the researcher is ‘zooming out’ in order to examine considerable. the wider picture. On the contrary, in reductionist thinking, Stage T5- It may be necessary to consider another, per- the problem is broken down into individual pieces, hoping to haps final, stage which is time-related. Because aging is a unravel systemic properties by studying these individual continual process, we may also need to assess the persistent pieces. In fact, it is unlikely that only one approach is going efficacy of the proposed treatment for all affected humans. to be helpful, but a combination of thinking methods should This must remain unfailingly favourable in the long-term. provide useful answers. The substantial and measurable health improvements of Reductionist models of aging fail to account for a number stage T4 must persist for an indefinite time-period [7]. of concepts that are associated with real-life complexity. One Rejuvenation biotechnologies (which aim to ‘restore such concept ‘Non-additive Determinism, more commonly youth’, i.e. combat the aging process) and of anti-aging known as ‘emergence’ [17] where a system is not simply medicine in general, are, on the whole, still at stage T1. A demarcated by the sum of all of its individual components specific treatment may indeed be effective in laboratory seen in isolation, but there are additional properties that add animals, but this treatment must be shown to make a persis- another layer of complexity in the system’s behaviour. In tent (not transient) positive health impact at the level of the this situation, emergence specifies that simply analysing in- human population (stage T5). Although each of the above dividual components of a system does not align with the be- stages may not be impossible to achieve, nevertheless in haviour of the system seen as a whole [18, 19]. practice, the totality of the problems seen from a systemic In addition to considering the properties of the individual thinking perspective makes the effectiveness of any rejuve- components of a system, we must also take into account how nation intervention much less promising [8]. biological and social factors define the behaviour of an or- Therapies aimed at established diseases of aging or any ganism. This is the concept of ‘Reciprocal Determinism’ other time-dependent loss of function, must not rely only on [18], where the behavior of the biological and social factors biomedicine but must take into account non-biomedical fac- interact in a complex way leading to results which may be tors such as behavioural, social, cognitive, psychological and unnoticeable when we study separately biological or social other environmental influences [9, 10]. elements. Instead, it is necessary to consider the combined With regards to aging, there is excessive reliance on an- effects of both the biological and the socio-cultural environ- other faulty logic, namely that research on animals may lead ment of the patient [3]. to significant benefits in humans. This logic is faulty because By considering the dynamics of the entire system (the of a variety of reasons [11]. One of these reasons is that the organism in association with the environment the organism health of human populations must be considered in associa- is in) we move to new and perhaps more promising domains tion with our environment, society, culture and other non- which examine the relationship between genes and society medical parameters. Human-specific phenotypes may be (social genomics) [20, 21] and the relationship between dissimilar to animal ones, and even mammal or higher ape genes and culture (gene-culture co-evolution) [22]. Social phenotypes are different than those of humans – in some genomics, as the term suggests, examines the effects of so- cases from 11% to 31% different [12]. It has been demon- cial stimuli and environmental challenges upon our genome strated that microRNAs in humans may have special func- [23]. Cole [23] states that: tions which outline significant differences between humans and other animal species [13]. MicroRNAs are relevant in “Systems-level capabilities emerge from groups of individual, socially sensitive genomes… and … this respect because they reflect environmental and epige- transcriptional biofeedback (that) empirically opti- netic effects such as societal influences on the DNA.