From Gerontology to Geroscience: a Synopsis on Ageing

From gerontology to geroscience: a synopsis on ageing

Piotr Paweł Chmielewski

Anthropological Review • Vol. 83(4), 419–437 (2020)

From gerontology to geroscience: a synopsis on ageing

Piotr Paweł Chmielewski

Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland

Abstract: Biological ageing can be tentatively defined as an intrinsic and inevitable degradation of biological function that accumulates over time at every level of biological organisation from molecules to populations. Senescence is characterised by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. With advancing age, all components of the human body undergo these cumulative, universal, progressive, intrinsic and deleterious (CUPID) changes. Although ageing is not a disease per se, age is the main risk factor for the development of a panoply of age-related diseases. From a mechanistic perspective, a myriad of molecular processes and components of ageing can be stud- ied. Some of them seem especially important and they are referred to as the hallmarks of ageing. There is compelling evidence that senescence has evolved as an emergent metaphenomenon that originates in the difficulty in maintaining homeodynamics in biological systems. From an evolutionary perspective, senescence is the inevitable outcome of an evolutionarily derived equilibrium between the amount of resources devoted to somatic maintenance and the amount of resources devoted to sexual reproduction. Single-target, single-molecule and disease-oriented approaches to ageing are severely limited because they neglect the dynamic, interactive and networking nature of life. These limitations notwithstanding, many authors promote single-target and disease-oriented approaches to senescence, e.g. repurposed drugs, claiming that these methods can enhance human health and longevity. Senescence is neither a disease nor a monolithic process. In this review, the limitations of these methods are discussed. The current state of biogerontology is also summarised.

Key words: age, ageing, age changes, biogerontology, gerontology, health, senescence

Introduction get where the pieces were’, but Death restores them to their place saying: ‘But I haven’t for- In The Seventh Seal by Ingmar Bergman, gotten’ and ‘No one escapes me’. Death asks Antonius: ‘Have you tricked me?’, These excerpts express fundamental and the knight replies: ‘Of course. You fell truths about human life and existence. into the trap’. On another occasion, Antonius Death is inevitable. Nature carefully knocks the chess pieces over and says: ‘I for- keeps its secrets, allowing us to wonder

Original Research Article Received: November 18, 2020; Revised: November 29, 2020; Accepted: December 1, 2020 DOI: 10.2478/anre-2020-0029 © 2020 Polish Anthropological Society 420 Piotr Paweł Chmielewski at its wonders. Like Antonius, we will of mortality. Longevity is a long duration never stop asking questions. Playing of life or just the length of life (Carnes chess with death, we can win a single 2011; Chmielewski et al. 2016b). Lon- battle, but does this mean that human gevity is considered a multifactorial ageing is not inevitable? trait that is determined by genetic back- In this review, I summarise the cur- ground, epigenetic alterations, the en- rent knowledge of ageing based on my vironment and lifestyle-related factors research and experience (Chmielewski such as diet, nutrition and behaviour. and Borysławski 2012, 2016; Chmielews- ki et al. 2015, 2016a, 2016b, 2017; Ch- When human ageing begins mielewski 2016, 2017, 2018, 2019, 2020a, 2020b; Chmielewski and Str- There has been considerable debate on zelec 2018, 2020). Currently, the world when biological ageing begins: at birth, of biogerontologists is divided into two conception or parental gamete forma- parties: one group believes that human tion (Milne 2006; Kinzina et al. 2019; ageing is something similar to a disorder Cohen et al. 2020b). Biochemists and that can be treated with drugs, whereas geneticists often consider ageing as the the second group considers ageing as a result of the accumulation of molecular continuum of life that is neither a treat- and cellular damage. The idea that the able condition nor a monolithic process. ageing process commences early in on- Many biogerontologists believe that age- togeny is grounded in the view that DNA ing is treatable (de Grey et al. 2002; Bla- damage accumulation most likely begins gosklonny 2018) or curable (Skulachev at parental gamete formation (Bocklandt 2011; Skulachev and Skulachev 2017). et al. 2011; Horvath 2013; Kinzina et al. In this article, arguments in favour of the 2019). Furthermore, senescent cells ac- opposite viewpoint are presented. cumulate in the body throughout ontogeny and they can contribute to organis- Ageing, lifespan and longevity mal senescence (Franceschi and Campisi 2014; Sikora et al. 2018). On the other Biological ageing can be defined as an hand, meaningful impacts of cellular se- ‘intrinsic and inevitable degradation of nescence are primarily later in life, i.e. biological function that accumulates over after ELS. Moreover, critical arguments time at every level of biological organi- have posited that growth, development sation from molecules to populations’ and maturation cannot be understood (Carnes 2011) or a ‘progressive loss of as ageing (Kaczmarek and Szwed 1997; function and fitness, which occurs during Rattan 2006; Carnes 2011; Chmielews- the extended period of survival beyond ki 2017; Kaczmarek and Wolański 2018; the essential lifespan (ELS)’. Lifespan is Arking 2019). defined as an individual’s observed dura- Thus, making a distinction between tion of life. Life expectancy at birth (e0) is developmental changes, which are pro- a key term that denotes the average num- grammed and adaptive, and age-chang- ber of years newborns may be expected es, which are non-programmed and to live under the death rates that prevail non-adaptive, would further our under- at different ages in a given population. standing of ageing dynamics. In 1959, Life expectancy is an important measure Strehler proposed five criteria, i.e. cumu- From gerontology to geroscience: a synopsis on ageing 421 lative, universal, progressive, intrinsic use the term homeodynamics (Lloyd et al. and deleterious (CUPID) changes, that 2001). It is important to note that terms must all be satisfied in order to assign like ‘dynamic homeostasis’ are errone- a given change in biological structure or ous as they imply that there is also ‘static function to senescence (Carnes 2011; homeostasis’, while homeostasis (in all Arking 2019). Nevertheless, it is of note biological systems) is understood as the that physiological decline commences dynamic interplay between external influ- early in human ontogeny. Therefore, it ences that may contribute in altering an is reasonable to predict that the accumu- organism’s internal environment and the lation of molecular damage starts early internal control mechanisms that oppose (Kinzina et al. 2019; Cohen et al. 2020b). such changes. Thus, adding the adjective Ageing is heterochron, meaning that dif- ‘dynamic’ to the term that refers to a dy- ferent biological systems begin to age at namic process makes little sense (Cohen different times. The ageing process also 2016). bears similarities with heterotrop, as age changes in different biological systems Healthy ageing: from disease- may follow different patterns. For example, the skin, vasculature and kidneys oriented to health-oriented begin to age relatively early, whereas approaches physiological brain ageing occurs at later stages of ontogeny. In fact, older adults Biological ageing occurs in spite of com- experience ageing at different rates, and plex processes and mechanisms for so- even in the same person different organs matic maintenance, repair and defence age at varying rates. (Rattan 2013). Since all molecular processes in biological systems are regulated Understanding ageing: the by genes and gene products, discovering ‘genes for ageing’, i.e. gerontogenes sensu concept of homeodynamics stricto, has been a popular theme in gerontology. To date, hundreds of putative Unlike non-living objects, living organ- gerontogenes have been identified. Nev- isms are able to respond, to counteract ertheless, it has been established that and to adapt to the internal and exter- gerontogenes sensu stricto do not exist, nal factors. The internal conditions of and there is no genetic programme spe- biological systems are not permanently cifically to cause ageing (Kirkwood 2005; fixed and they are not ‘at equilibrium’. Kowald and Kirkwood 2016). If ageing The notion of ‘stability through constan- were genetically programmed, or at least cy’ does not sufficiently take into- ac quasi-programmed, it could be treat- count the dynamic nature of information ed like a disease (Skulachev 2011; Bla- and interaction networks that underlie gosklonny 2018). Instead, ageing is an the inherent complexity of biological emergent metaphenomenon. Although systems. Given that living organisms are ‘ageing as a disease’ label can attract dynamic entities in constant flux, it can the attention of investors, it totally dis- be argued that the biological term homeo- regards the accumulated research in the stasis is problematic (Witkowski 2009). field. Numerous sound arguments have Therefore, it would be more judicious to been advanced against the idea that age- 422 Piotr Paweł Chmielewski ing is a disease (Hayflick 2016; Rattan der to extend human lifespan. These in- 2016; Chmielewski and Strzelec 2020). clude: (1) gene therapy, (2) epigenetic Although ageing is not a disease per reprogramming, (3) stem cell therapies, se, age is a major risk factor for the devel- (4) elimination of senescent cells and opment of a wide spectrum of age-related dysfunctional mitochondria and (5) CR diseases (ARDs). The rate of human age- mimetics and repurposed drugs such as ing can be accelerated by an unhealthy rapamycin and metformin. However, it diet and lifestyle (Kirkwood 2005). Many is health that should be enhanced, not authors suggest that human senescence just lifespan (Chmielewski et al. 2016b; can be effectively postponed in the fu- Olshansky 2018). Ageing studies focus ture (López-Otín et al. 2013; Kennedy on improving lifespan. Currently, our et al. 2014; Longo et al. 2015; Campisi arsenal of possible interventions and et al. 2019), as the rate of senescence methods for life extension is brimming can be modulated, at least to some ex- with promising candidates. Neverthe- tent (Cohen 2016), by genetic, dietary, less, improving healthspan in parallel is biochemical and pharmacological meth- crucial for reducing chronic disease bur- ods, although other researchers have den (Kennedy et al. 2014). Furthermore, challenged this claim (Hayflick 2003, one of the greatest challenges in current 2004, 2007a, 2007b; Carnes et al. 2013; biogerontology is to translate the infor- Hayflick 2016). The empirical data show mation gathered from studies performed that ageing is not an immutable process, on animal models to humans (Rattan but a dynamic and malleable phenome- 2020). Other biogerontologists assert non that can be affected by a variety of that human longevity cannot be effec- influences. tively enhanced (Hayflick 2003, 2004, It is worth recalling that single gene 2007a, 2007b, 2016). mutations can extend lifespan in worms (Kenyon 2010, 2011). Cynthia Kenyon From gerontology to discovered that mutations in a gene called daf-2 double lifespan in Caenorhab- geroscience ditis elegans (in hermaphrodites). In the other sex, the same mutation increases Gerontology is the study of the biolog- longevity more than 6-fold. In human ical, social, psychological, cognitive and terms, this is equivalent to 500 years. anthropological aspects of ageing. This It has also been demonstrated that re- term was coined by Ilya Mechnikov in programming erases cellular markers of 1903. Biogerontology, which is also re- ageing in human cells (Ocampo et al. ferred to as the biology of ageing, is the 2016). This amelioration of age-asso- study of the physiological mechanisms ciated features of the ageing phenotype of ageing and the evolutionary aspects of highlights the role of epigenetic dysreg- senescence. ulation as a driver of mammalian ageing. Geriatrics is a branch of medical sci- These unexpected findings indicate that ence concerned with the prevention, ageing is a dynamic and plastic process diagnosis and treatment of diseases in that is amenable to intervention. More- older people. Recently, a new interdis- over, there are a number of potential ciplinary subfield called geroscience has methods that could be employed in or- emerged. This subfield is at the interface From gerontology to geroscience: a synopsis on ageing 423 of biogerontology and geriatrics. Like Furthermore, there is marked dis- biogerontology, geroscience is based on agreement on the most fundamental the functional understanding of ageing questions in the field such as: (1) when as the risk factor for the development ageing begins, (2) how to measure its of a panoply of ARDs and geriatric syn- rate, (3) how to retard the ageing pro- dromes. Geroscience aims to understand cess, (4) how to prevent ARDs, as well the links between normal ageing and the as several other pressing issues (Ch- wide spectrum of ARDs based on ex- mielewski 2020a; Cohen et al. 2020a). perimental data and epidemiological re- Based on own research and experience, I search (Kennedy et al. 2014; Franceschi have compiled a list of fifteen questions et al. 2018). This subfield is focused on that can be considered to be the most the molecular biology of ageing. Many fundamental issues in current biogeron- biogerontologists argue that a deeper tology (Table 1). The possible answers understanding of these cell-molecular have been divided into three groups: mechanisms of ageing will be crucial ‘yes’ (to express total agreement), ‘part- in the development of therapeutic ap- ly/in a sense’ (to express the idea that proaches for the widespread panorama the question is complex or imprecise, of ARDs. or that we are not ready to provide a Ageing is a fascinating topic that has straight answer to the question) and ‘no’ captured the interest of many research- (to express strong disagreement). The ers from a diverse range of disciplines, authors that have been treated as re- ranging from biochemistry, genetics, cell spondents are noted biogerontologists, biology, bioinformatics, biophysics, med- biochemists, geneticists and researchers icine, endocrinology, epidemiology, evo- who have published hundreds of sci- lutionary biology, ecology, systems biol- entific articles on ageing. Two methods ogy and biodemography. A fundamental have been employed in order to increase challenge has been to integrate both the reliability of such a juxtaposition of empirical data and theoretical constructs possible answers that can be considered that have emerged from these different too arbitrary or subjective: these authors subfields and perspectives, as well as to have already provided tentative answers establish a common language and defi- and they are strident advocates of their nitions. The science of ageing has made own views. great advances in the understanding of For example, Question No. 1, i.e. ‘Can physiological and evolutionary aspects ageing be programmed?’ has two possible of senescence. Although biogerontology answers: Yes and No, and only the strident has matured as a scientific discipline and advocates of these two rival theories are our knowledge has advanced (Holliday cited (Longo et al. 2005; Skulachev and 2006, 2009; Rattan 2006; Hayflick 2007a, Longo 2005; Skulachev and Skulachev 2007b), the diverse nature of ageing has 2017) for ‘yes’ and (Kirkwood and Melov not been fully understood. One possible 2011; Kowald and Kirkwood 2016) for reason for this is due to the heterogene- ‘no’, even though it is generally agreed ity and complexity of mechanisms and that the standard theoretical models of processes contributing to ageing (Jones ageing rule out the possibility that age- et al. 2014; Cohen 2018; Cohen et al. ing is programmed. Therefore, the an- 2020a, 2020b). swer to this question is skewed towards 424 Piotr Paweł Chmielewski

Table. 1. Big names and the odd science of ageing. There is marked disagreement on the most fundamental questions in the field Yes Partly/In a sense No 1. Can ageing be programmed? Longo et al. 2005; Kirkwood and Melov 2011; Skulachev and Skulachev 2017 Kowald and Kirkwood 2016 2. Can ageing be programmed through hormonal cascades in some species as a rare exception from the general rule? Cohen 2018 3. Is it true that many animals do not age? Finch 2009; Sikora 2014; Hayflick 2007b, 2016; Cohen 2018 Holliday 2009 4. Can evolution favour ageing in sexually reproducing animals? Lenart et al. 2018 Kirkwood 2005 5. Is mammalian ageing molecularly orchestrated? van Heemst et al. 2005 Blagosklonny 2008 6. Is ageing driven by genes and/or biochemical pathways for ageing, e.g. mTOR and insulin/IGF-1 signalling? Longo et al. 2005; Bartke et al. 2002 Kirkwood 2005 Blagosklonny 2008 7. Are there ‘enemies within the body’ that can contribute to human senescence? Longo et al. 2005; Franceschi and Campisi 2014 Rattan 2006 Blagosklonny 2008 8. Is the Theory of Molecular Entropy of Ageing fundamentally wrong? Kirkwood 1999; Hayflick 2007a, 2016; Mitteldorf 2010 Demetrius 2013 9. Is the Free Radical Theory of Ageing (FRTA) specious? Piotrowska and Bartnik 2014 Kirkwood and Kowald 2012 10. Does human ageing begin early in ontogeny, e.g. at conception or at parental gamete formation? Bocklandt et al. 2011; Cohen et al. 2020b Rattan 2006 Horvath 2013 11. Is the distinction between senescence and age-related pathologies artificial and elusive? Holliday 2006, 2009; Hayflick 2016; Rattan 2016 Kirkwood 2011 12. Is human ageing an inevitable process (a stochastic process that cannot be postponed with drugs)? Hayflick 2003, 2004; Kennedy et al. 2014 Carnes et al. 2013 13. Can human ageing be effectively postponed in the future? Kirkwood 1999; Rose 1999; Cohen 2016 Hayflick 2003, 2004; de Grey et al. 2002; Carnes et al. 2013 Kennedy et al. 2014 14. Is there a biological limit to human longevity? Carnes et al. 2003; Dong et al. 2016 15. Is our understanding of biological ageing almost complete? Holliday 2006, 2009; da Costa et al.2016a, 2016b; Hayflick 2007a, 2007b Cohen 2018 From gerontology to geroscience: a synopsis on ageing 425 the negative, as there is neither a rigid versal’ (de Grey et al. 2002); Not exactly programme for ageing nor gerontogenes as ‘there is little hope that rejuvenation sensu stricto, i.e. genes that cause ageing. therapies will be able to do much more The idea of ‘quasi-programmed ageing’ is than serve as a speed bump during the omitted for two reasons: firstly, it is too ageing process’ (Cohen 2016); and Defi- simplistic (Zimniak 2012; Rattan 2020); nitely not as ‘No intervention will slow, secondly, the author of this paradigm stop, or reverse the ageing process in hu- states that ageing is ‘quasi-programmed’ mans’ (Hayflick 2004). It can be argued and ‘non-programmed’ simultaneously. that authors who use phrases such as ‘it Thus, it can be argued that this author certainly can’ and ‘no intervention will has considerably diminished the value of ever do something’, already know the an- his own work. swers. These authors approach the prob- Question No. 3 refers to the idea that lem from very different perspectives, i.e. ‘many animals do not age’, which is a di- evolutionary and mechanistic. rect quote from Cohen (2018). In fact, Question No. 14, i.e. ‘Is there a bio- many noted biogerontologists share this logical limit to human longevity?’ has idea (Austad 2009; Sikora 2014; Kow- one direct answer, which is based on ald and Kirkwood 2016). The concept of the hypothesis that human longevity is negligible senescence was introduced by predetermined and limited, which has Caleb Finch (2009). Finch’s idea includ- received empirical support (Carnes et al. ed other animals and became one of the 2003; Dong et al. 2016). Nonetheless, most promising discoveries in the field of other authors argue that human lifespan ageing (Austad 2009). Many evolutionary can be indefinite, at least in theory (Rose biologists believe that human ageing can 1999), as maintenance mechanisms of be arrested at a given age, at least in the- the body and human physiology can be ory (Kirkwood 1999; Rose 1994, 1999), optimised (Kirkwood 1999). For exam- as human senescence naturally ceases ple, da Costa and associates (2016b) at approximately 95 years of age (Rose, claim that: ‘an optimization of these personal communication; Mueller et al. processes could, in theory, make life in- 2011). However, it is obvious that hu- definite’. Thus, the idea that humans man ageing does not stop (Finch 2009). can become virtually immortal persists Nearly all known animals undergo age- in the scientific literature, despite com- ing which cannot be postponed, stopped pelling evidence to the contrary (Dong or reversed (Hayflick 2003, 2004, 2007a, et al. 2016). Holliday (2009) argues that 2007b, 2016). Holliday (2009) contend- the idea that human ageing can be effec- ed that ‘there is no mystery in the fact tively postponed thanks to anti-ageing that all animals age’ (page 226). drugs and interventions is scientifically Question No. 13, i.e. ‘Can human ungrounded. Both the empirical data and ageing be effectively postponed in the theoretical models have proved the scep- future?’, has three different answers: tics right (Hayflick 2003, 2004; Carnes et Yes. ‘In theory, it certainly can’ (Kirk- al. 2008, 2013; Cohen 2016; Dong et al. wood 1999; Rose 1999; da Costa et al. 2016; Chmielewski 2020a; Rattan 2020). 2016a, 2016b)’ and yes since ‘all the It is of note that all these answers are key components of mammalian ageing definitely not true as they contradict each are indeed amenable to substantial re- other. Ageing research has burgeoned in 426 Piotr Paweł Chmielewski the last decade. Consequently, biogeron- latter focus on the evolutionary explana- tology has made remarkable progress in tions and resolve the apparent paradox understanding the physiological mech- that a phenomenon has evolved that is anisms of ageing (Holliday 2006, 2009; non-adaptive at the individual level. It Hayflick 2007a, 2007b). However, de- has been hypothesised that ageing might spite the growing knowledge of these be a more fundamental aspect of cellular mechanisms, there are still a number organisms than assumed thus far (Acker- of questions that remain unanswered. mann et al. 2007), as the mechanisms of Therefore, some authors argue that the ageing are expected to operate in a wide science of ageing is ‘very much at its in- range of organisms, suggesting that age- ception’ (da Costa et al. 2016a) as ageing evolved early in the history of life. ing is ‘poorly understood’ (Cohen 2018). Several years ago, a modern classifi- In fact, little is known about how these cation of these theories was presented mechanisms interact to shape the trajec- and discussed (Sikora 2014; Chmielews- tory of senescence and the onset of ARD. ki 2017). An alternative classification, Furthermore, the scientific literature of- proposed by Trindade et al. 2013 and fers ‘surprisingly little’ insight into the da Costa et al. 2016a, is summarised in key mechanisms of ageing, especially in Fig. 1. Causality theories consist of three the context of geroscience (Melov 2016). types of explanations: (1) entropy-based Thus, more research is needed in order theories, (2) stochastic damage theories, to understand how to enhance human such as the Free Radical Theory and the healthspan, not just lifespan (Olshansky DNA Damage Theory and (3) sudden 2018; Chmielewski 2020a). With this in death phenomena, which include acci- mind, the general theory of health needs dents, cannibalism, fatal reproduction, to be developed, and the science of age- semelparous reproduction, as well as ing awaits such a theoretical framework. apoptosis in unicellular organisms. For many biogerontologists, ageing is an However, it should be remembered inevitable phenomenon that cannot be that other classifications of ageing effectively postponed or reversed (Hay- and death theories exist (Kaczmarek flick 2003, 2004, 2007a, 2007b, 2016; and Szwed 1997; Kirkwood 2005; Mi- Carnes et al. 2008, 2013; Carnes 2011; kuła-Pietrasik et al. 2014; Sikora 2014; Cohen 2016; Chmielewski 2019, 2020a). Chmielewski 2017), with marked disagreement on the most fundamental Theories of biological ageing: issues in the field (Table 1). Given that the hallmarks of ageing are intertwined an ever-evolving field processes (López-Otín et al. 2013; Ken- nedy et al. 2014; Mikuła-Pietrasik et al. In order to understand the nature of age- 2014), a network theory of ageing is a ing, a number of theoretical frameworks more progressive idea than an aspect have been developed. In general, the the- theory of senescence. Recently, a uni- ories of ageing fall into two categories: fied theory of senescence encompassing mechanistic theories address questions genes, proteins, free radicals and the of how ageing and death occur in differ- performance of maintenance and repair ent species, whilst evolutionary theories systems has gained general acceptance explain why ageing evolved. Thus, the (Rattan 2006). From gerontology to geroscience: a synopsis on ageing 427

Fig. 1. An alternative classification system for ageing and death theories (after Trindade et al. 2013 and da Costa et al. 2016a, modified). In general, the theories fall into two categories: causality and evolutionary. Causality theories consist of three types of explanations: (1) entropy-based theories, (2) stochastic damage theories and (3) sudden death phenomena. Stochastic damage theories propose that ageing is caused by the intrinsic and progressive accumulation of molecular damage over time, leading to an increasing risk of death. The standard models predict that ageing is due to the summation of randomly acquired deleterious effects, i.e. CUPID changes. Accordingly, ageing results from the gradual lifelong accumulation of molecular damage. These standard theories include the Mutation Accumulation The- ory, the Antagonistic Pleiotropy Theory and the Disposable Soma Theory (DST). Nevertheless, other classification systems include the Developmental Theory of Ageing (DTA), the Theory of Molecular Entropy and the Theory of Phenoptosis

Programmed ageing: The concept that biological ageing is phenoptosis revisited programmed and determined, or at least predetermined, is so attractive and ap- The concept of programmed ageing was pealing that it persists among research- developed as early as 1889 by August ers in spite of compelling evidence to Weismann. In brief, this hypothesis states the contrary. Many authors argue that it that: (1) ageing corresponds with an ad- is still a matter of debate whether bio- aptation in nature, (2) evolution favours logical ageing is a programmed process, ageing individuals over non-ageing indi- a quasi-programmed (non-adaptive) viduals and (3) ageing fulfils a biological phenomenon, or merely a consequence function because it eliminates aged, ill of the accumulation of random molecu- and worn-out individuals from the group, lar damage (Sikora 2014; da Costa et al. thereby providing living space, food and 2016b; Lenart et al. 2018; Schmeer et al. other resources for the offspring. At the 2019). end of his life, Weismann became scepti- According to the theory of phenop- cal and recanted this idea. tosis, which was formulated in 1999 by 428 Piotr Paweł Chmielewski

Vladimir Skulachev, ageing is an atavistic stood as a process of nature, ‘wants us to and mitochondria-mediated programme die’ because we generate more costs than that consists in gradual degeneration and benefits as we age. This statement sounds self-destruction of the body. In this view, similar to the idea that ‘the force of gravity ageing resembles a programmed phe- wants us to fall over a precipice’, which is nomenon that results from the accumu- obviously false and hardly anybody would lation of detrimental changes, damage espouse that idea. At the same time, the and toxins generated by the same main- concept of programmed ageing is popular tenance mechanisms that sustain life. due to its parsimony. Many authors argue Mitochondria are the key energy-pro- that it is still a matter of debate whether ducing organelles. These organelles play ageing is a programmed phenomenon or a crucial role in a variety of biochemical merely a stochastic process (Sikora 2014; processes. With advancing age, however, Schmeer et al. 2019). Although a vast ma- mitochondrial dysfunction occurs, and jority of biogerontologists do not share this decline has been associated with the idea that ageing evolved for its own both normal ageing and the development sake (Kirkwood and Melov 2011; Kowald of a wide range of ARDs. Hence the idea and Kirkwood 2016), alternate views ex- of quasi-programmed ageing, i.e. prede- ist. At one extreme, Skulachev and associ- termined ageing, is not without merit ates claim that ageing is an atavistic pro- if we understand it from a mechanistic gramme that fulfils a biological function perspective. (Longo et al. 2005; Skulachev and Longo According to some authors, phenop- 2005; Skulachev and Skulachev 2017). tosis could be an evolutionarily pro- While other eminent researchers assert grammed mechanism that culls out aged, that ageing is not an adaptation, it is defi- ill and damaged individuals, which is nitely an inherent biological programme analogous to apoptosis, i.e. programmed (Declerck and Vanden Berghe 2018) or at cell death (PCD). In brief, cells are least a quasi-programme (Blagosklonny cheaper, less important and subordinate 2008, 2018). Recently, the Developmen- to the body. Such biological entities are tal Theory of Ageing (DTA) has been described as units of a lower order. Ac- reintroduced (Maklakov and Chapman cording to the Samurai law of biology, a 2019). lower order units should be eliminated Let us hypothesise that biological to secure the survival of units of a higher ageing is genetically programmed and order. In particular, abnormal, damaged the genes for ageing exist. This view or cancer cells should be killed as they might seem optimistic as sophisticated threaten the survival of the whole body. interventions can interfere with the un- With age, all somatic cells accumulate derlying mechanisms that appear to be damage, which can be understood as common to multiple symptoms. In this a consequence of metabolic processes. view, ageing can be treatable or curable Similarly, a single organism seems less just like a disease. However, if a ‘cure’ important at a group level, often subor- for ageing were developed in the near dinating to the group, just like cells are future, the concern of rising population subordinate to the body. would not amount to a marked increase Proponents of programmed ageing of- for a considerable period. However, ten argue that evolution, which is under- overcrowding would eventually become From gerontology to geroscience: a synopsis on ageing 429 detrimental to the human population, Non-programmed ageing: showing that evolution really ‘wanted us molecular entropy to die’. Nonetheless, there have been many Traditionally, ageing was understood as critiques of the idea of adaptive and al- an inevitable outcome of chemical dam- truistic ageing. Firstly, special circum- age and entropy. In fact, the idea that bi- stances need to exist for this strategy, ological ageing is due to entropy is very i.e. adaptive and altruistic senescence, old and widespread. It is noteworthy that to be an evolutionarily stable strategy all organisms are thermodynamically (ESS), let alone the only ESS (Kirkwood open systems, whereas the Second Law and Melov 2011; Kowald and Kirkwood of Thermodynamics is concerned with 2016). This argument derives from Evo- closed systems. Moreover, all organisms lutionary Game Theory and disproves must be liberated from the Second Law the idea of adaptive and altruistic age- of Thermodynamics in order to exist. ing. Secondly, organismal senescence Failure to resist entropy ensures death. ‘is, prima facie, quite different from other Since biological organisms have the abil- programmed biological processes such ity to escape entropy during their life cy- as development and apoptosis’ (Cohen cle, it is unclear why entropy is relevant. 2015). Cohen (2015) argues that ageing Although the theory of entropy can ex- is too heterogeneous across individuals plain the complex processes of decay and to be a programme and the ageing pro- death of organic matter, it cannot explain cess takes too long to be a programme. why humans age. ‘Development is also slow, but making Biogerontologists argue that if entro- an organism is difficult. Making it die py were a real cause of biological ageing, is, biologically, a simple task’. A simple life from its beginning would be subject to task cannot take several decades. Thirdly, deterioration with time, which indicates there is no empirical evidence that geron- that the theory of entropy is specious and togenes exist (Kowald and Kirkwood invalid (Kirkwood 1999). Furthermore, 2016) or that ageing fulfils a biologi- it can be argued that no convincing ar- cal function (Rauser et al. 2009; Cohen guments or theoretical models have been 2015). Finally, in humans and in other presented in order to verify role of entro- sexually reproducing species, the surviv- py in biological ageing (Chmielewski and al of offspring depends upon the survival Borysławski 2016).Thus, it seems that of their parents and alloparents. If age- the theory of entropy is more suitable ing were an adaptation or a phenomenon for explaining the degradation of dead resembling an adaptation (Lenart et al. organic matter (Mitteldorf 2010). Sur- 2018), then it would have the effect in prisingly, several modern classifications limiting the longevity of older individu- of ageing and death theories embrace the als, thereby increasing the likelihood of idea that senescence is due to molecu- death of their offspring. In other words, lar entropy (Trindade et al. 2013; Siko- if programmed death mechanisms oper- ra 2014, da Costa et al. 2016a, 2016b). ate to kill the mother, then the survival Many noted biogerontologists argue that of her progeny is also endangered. This molecular entropy is the real cause of suggests that the idea of programmed, biological ageing (Hayflick 2003, 2004, adaptive and altruistic ageing is flawed. 2007a, 2007b, 2016; Demetrius 2013), 430 Piotr Paweł Chmielewski which is rather surprising as it is gener- accumulate damaged cells and lose our ally agreed that entropy has no bearing ability to replace them with new cells. In- on biological ageing (Kirkwood 1999; terestingly, the sheer number of cells in Mitteldorf 2010). Are there any hidden the human body can predict the relation arguments in favour of this theory? between body size and cancer with no It may seem that ageing is due to need to suggest additional factors (Nun- increasing disorder (entropy) as all bio ney 2018). Although cells are constantly logical systems move towards increas- repairing and maintaining themselves via ing disorder with time. Even if we have intake of free chemical energy from food a perfect system to start with, molecules and by dumping their waste entropy back and cells become damaged and disor- into the surroundings, individuals within dered due to the complex interaction be- the same species that have a considerable tween genes and the environment. Bio- amount of extra cells are more prone to logical organisms are affected by external DNA damage and cancer. This is because forces and energy that can damage mol- more cells in the body increase the risk ecules and cells. Samaras (1974) points factor for DNA damage and mutations. out that the human body is a complex system that is composed of subsystems, Disposable Soma Theory: an i.e. molecules, cells, tissues, organs, and processes. The human body has an op- update timum configuration of parts and inter- relationships that involve roughly 1014 The Disposable Soma Theory (DST) con- cells (Kłyszejko-Stefanowicz 1998; Bian- stitutes a physiologically based evolu- coni et al. 2013). Although, the human tionary model that describes ageing as a body share similarities with inanimate stochastic process that occurs as a result systems, it is more than a configuration of evolved limitations in somatic mainte- of subsystems. Moreover, biological sys- nance (Kirkwood 1977, 2005). Recently, tems are different from non-living object. this prominent theory has been expand- The theory of molecular entropy ed to all unicellular lineages (Teulière et predicts that internally and externally al. 2020), thereby falsifying the claim caused disorder is never fully correct- that ageing can be programmed because ed by our internal repair and defence bacteria undergo bacterial senescence systems. In a closed system without an (cf. Mitteldorf 2010). Thus, the argu- intake of restorative energy from an ex- ments in favour of programmed ageing ternal source, life would quickly become are nebulous and implausible. disordered and die. However, the human According to DST, ageing occurs as a body is not a closed system, and we ob- result of evolved limitations in somat- tain ordered energy from the physical ic maintenance, as the more an animal world. Human bodies are also capable of expends on sexual reproduction and removing dead or damaged cells and as- growth, the less resources it can invest sociated waste products. Thus, humans in somatic maintenance, and vice versa are able to restore much of our internal (Kirkwood and Holliday 1979; Kirkwood disorder for approximately 100 years and Rose 1991; Kowald and Kirkwood (Dong et al. 2016). Unfortunately, this 2016). Thus, there are evolutionary process is not perfect and we gradually trade-offs between the allocation of re- From gerontology to geroscience: a synopsis on ageing 431 pairing mechanisms and somatic mainte- production are relatively low in humans nance, and the allocation of resources for (Gurven et al. 2016). sexual reproduction. Maintenance mech- However, some critiques of DST have anisms and reproduction use the same been raised. According to other authors, resources, and the body (soma) is merely DST cannot explain the effects of calor- a ‘disposable carrier’ for genes that use ic restriction (CR) on lifespan in animal the body to propagate themselves. Af- models as it predicts that energy short- ter sexual reproduction has taken place, age should result in a shorter lifespan as the body becomes redundant, whereas resources available for somatic mainte- the genetic material lives. Several stud- nance are significantly reduced (Kyriazis ies have corroborated this theory in both 2020). In fact, the opposite is true. DST laboratory experiments and anthropo- is useful here as it predicts that: (1) the logical investigations (Ziomkiewicz et al. allocation of resources is affected by nu- 2016; Jasienska et al. 2017). trient availability in short-lived animals; It is generally accepted that sexual re- (2) the shortage of energy in the form of production is costly from both physiolog- food signals a situation that will result in ical and behavioural perspectives. DST lower offspring survival; and consequent- provides an elegant theory for explain- ly, (3) resources are redirected from re- ing the phenomenon known as ‘negligi- production to somatic maintenance and ble senescence’. For example, the Hydra repair, as the probability of the survival is a cnidarian that does not have a true of these offspring is significantly reduced ‘soma’. Therefore, it is virtually immor- due to physical hardships and environ- tal in protected environments, but this mental challenges (Kirkwood et al. 2000; is true only for its asexual form (Austad Chmielewski et al. 2016b). 2009; Cohen 2018). In sexually repro- According to these standard models, ducing animals, there are evolutionary CR and CR mimetics will not enhance trade-offs between growth and reproduc- longevity in long-lived species such as tion early in life and resources that are humans and other primates (Demetrius available for somatic maintenance at lat- 2005; Le Bourg 2006; Shanley and Kirk- er stages of ontogeny. This is why ageing wood 2006). It has been established that evolves. According to DST, ageing cannot CR extends lifespan in multiple species be programmed as it is non-adaptive at (Zid et al. 2009), including long-lived the individual level (Kirkwood 2005; species. According to Kirkwood, there Kowald and Kirkwood 2016). Standard are very good grounds to believe that any evolutionary models explain that age- effect of CR on lifespan in non-human ing is tuned by relaxation of natural se- primates is likely to be extremely mod- lection, which means that ageing does est, if it exists at all (cf. Austad 2012); not occur in species that rely exclusive- for humans, an even more extreme state- ly on symmetrically fissile reproduction ment could be made. According to oth- (Rose 1994). Interestingly, DST enables er researchers, CR can enhance human us to understand why humans are long- health and longevity, but its effect is like- lived primates. It should be noted that ly to be minor compared with the effects resources that are available for somatic observed in short-lived animals. More- maintenance are surplus to requirements over, CR is problematic in humans due to (Kirkwood 1977), and health costs of re- numerous side-effects. Therefore, some 432 Piotr Paweł Chmielewski researchers believe that a future drug Rattan 2020). ‘Anti-ageing’ medicine has could imitate the benefits of CR, there- the following limitations that should be by by-passing this physiological hurdle acknowledged: (1) single-target and dis- (Ingram and Roth 2011, 2015). Howev- ease-oriented approaches to senescence, er, other biogerontologists are sceptical such as repurposed drugs, are severely as to the therapeutic usefulness of CR limited as they neglect the dynamic, in- mimetics and other ageing-modulating teractive and networking nature of life; drugs (Olshansky et al. 2002; Hayflick in other words, biological entities, such 2003, 2004; Carnes et al. 2013). as cells, do not operate as machines; (2) Another critique of DST is that if sex- ageing is not driven by any underlying ual reproduction is costly in terms of hu- mechanism, hence the effectiveness of man longevity, the theory should identify a single method for slowing down age- the molecular mechanisms to which an ing, such as CR/DR, CR mimetics, se- organism shifts energy to somatic repair nolytics or mTOR inhibitors, is likely over reproduction. This is because this to be extremely modest, if it exists at transition should be understood in order all; (3) although the rate of ageing can to improve health in people with high be accelerated by single gene mutations, lifelong reproductive effort. Neverthe- epigenetic alterations or an unhealthy less, it is generally accepted that sexual diet and lifestyle, no such interventions reproduction is a costly mechanism. In- have yet been identified which effective- creased reproduction can unfavourably ly postpone human senescence; (4) the alter the metabolism of lipids (Hansen idea that physiological processes can be et al. 2013) and is associated with great- optimised to make life indefinite is prob- er oxidative stress (Ziomkiewicz et al. ably specious; (5) single-target and dis- 2016). Other arguments against DST ease-oriented approaches can delay the seem problematic and invalid (Kowald age at death but they cannot effectively and Kirkwood 2016). postpone senescence; (6) current ‘anti-ageing’ medicine is fraught with naive Limitations of single-target and assumptions and extrapolations (Rattan 2020) that are unrealistic and fraudulent disease-oriented approaches to (Holliday 2009). human ageing Conclusions The dream of fending off old age and natural death is as old as recorded histo- Biological ageing is considered an inher- ry. The science of ageing is linked to the ent, dynamic and emergent metaphe- idea that various pharmacological and nomenon, i.e. the collection of CUPID dietary interventions can help effective- changes, that leads ageing organisms ly postpone ageing and delay the onset towards eventual mortality. The concept of ARDs (López-Otín et al. 2013; Ken- of ageing as a single, monolithic, well de- nedy et al. 2014; Franceschi et al. 2018). fined and treatable process has hindered However, biogerontologists are becom- progress in biogerontology. Thus, it can ing increasingly aware of the limitations be argued that ageing sensu stricto does of single-target and disease-oriented ap- not exist (cf. Cohen et al. 2020b). More- proaches to ageing (Chmielewski 2020a; over, mechanisms and processes contrib- From gerontology to geroscience: a synopsis on ageing 433 uting to the diversity of ageing across Bartke A, Campisi J, Heward C, McCarter the tree of life are highly complex and RJM, Stock G. 2002. Time to talk SENS: heterogeneous. There is neither a com- critiquing the immutability of human ag- mon underlying mechanism nor a genet- ing. Ann NY Acad Sci 959:452–62. Bianconi E, Piovesan A, Facchin F, Beraudi A, ic or epigenetic programme for ageing. 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