ISSN 10623604, Russian Journal of Developmental Biology, 2013, Vol. 44, No. 6, pp. 336–341. © Pleiades Publishing, Inc., 2013. Original Russian Text © A.N. Khokhlov, 2013, published in Ontogenez, 2013, Vol. 44, No. 6, pp. 434–440.
DISCUSSIONS
Decline in Regeneration during Aging: Appropriateness or Stochastics?1 A. N. Khokhlov Evolutionary Cytogerontology Sector, School of Biology, Moscow State University, Moscow, 119991 Russia email:
[email protected] Received May 9, 2013; in final form, June 25, 2013
If you want to make God laugh, tell Him your theory of aging. Anonymous Abstract—There is a standpoint according to which the suppression of the ability of cells in a multicellular organism to proliferate, taking place during aging, as well as the corresponding decline in the regenerative capacities of tissues and organs, is caused by the specialized mechanisms having emerged in the evolution that decrease the risk of malignant transformation and, thereby, provide for protection against cancer. At the same time, various macromolecular defects start to accumulate in senescent cells of the body, which, on the con trary, elevate the probability for malignant transformation of these cells. Thus, according to the mentioned concept, the restriction of cell proliferation is a doubleedged sword, which, on the one hand, decreases the probability for malignant tumor development in young age and, on the other hand, limits the lifespan due to accumulation of “spoiled” cells in old age. However, it remains unclear why normal human cells placed under in vitro conditions and thus having no mentioned “anticancer” barriers, which function at the body level only, NEVER undergo spontaneous malignant transformation. In addition, it is unclear how the freshwater hydra escapes both aging and cancer, as it under certain conditions contains no postmitotic and senescent cells at all and under these conditions (excluding the need for sexual reproduction) can live almost indefinitely, pos sessing a tremendous regenerative potential (a new organism can emerge from even 1/100 part of the old one). Presumably, the restriction of cell proliferation in an aging multicellular organism is not the result of a certain special program. Apparently, there is no program of aging at all, the aging being a “byproduct” of the program of development, whose implementation in higher organisms necessarily requires emergence of cell popula tions with a very low and even zero proliferative activity, which actually determines the limited ability of the corresponding organs and tissues to regenerate. On the other hand, the populations of highly differentiated cells incapable or poorly capable of reproduction (e.g., neurons, cardiomyocytes, and hepatocytes) are the particular factor that determines the normal functioning of higher animals and humans. Even regeneration of such organs with the help of stem cells may interfere with the necessary links in elaborate systems. The reductionism (“everything is determined by adverse changes in individual cells”), which has recently become widespread in experimental gerontological research, has brought about several model systems for studying the aging mechanisms in isolated cells (Hayflick phenomenon, stationary phase aging model, cellular kinetic model for testing of geroprotectors and geropromoters, etc.). However, it currently seems that data obtained using such models are inappropriate for an automatic extrapolation to the situation in the whole body. Pre sumably, impairments in regulatory processes functioning at the neurohumoral level are the major players in the mechanisms underlying aging of multicellular organisms rather than a mere accumulation of macromo lecular damage in individual cells. It cannot be excluded that a disturbance of such regulation is the particular reason for the abnormal INCREASE in proliferation intensity of some cell populations that are frequently observed in old age and that lead to senile acromegaly and development of numerous benign tumors. It looks like the quality of CONTROL over cells, organs, and tissues becomes poorer with age rather than the quality of the cells themselves, which leads to an increase in the death rate. Keywords: aging, regeneration, program, cell proliferation, cell aging, cancer DOI: 10.1134/S1062360413060040 1
The ability of tissues and organs to regenerate in the overwhelming majority of multicellular organisms declines with age (or, more precisely, in aging; see
1 The paper is based on the plenary lecture given by the author at the
international conference “Regenerative Medicine: Topical Issues” (October 4–5, 2012, Kyiv, Ukraine).
below). As a rule, such a decline is determined by a decrease in the ability of the corresponding body cells to proliferate (Beausejour and Campisi, 2006; Macieira Coelho, 2011), although cell proliferation is not the only process that determines the efficiency of regenera tion. Correspondingly, many gerontological concepts
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imply that the agerelated deterioration in regenerative capacity of the body is the particular factor that causes aging. It should be emphasized that in this case we speak about a classic definition of aging as the set of various agerelated changes in the organism that lead to an increase in the probability of its death. If the probability of individuals to die (measurable only at the level of population and determined by the ability to withstand various adverse factors of both exogenous and endoge nous origins, in particular, by the ability to regenerate) is rather high although it does not change with time, then we are dealing with nonaging organisms (or more precisely—the organisms that show no aging), which, however, still have a rather short lifespan (Khokhlov, 2010b, 2013). On the other hand, the aging organisms with a very low probability of death may live extremely long creating illusion of their “immortality.” This phe nomenon was called by Caleb Finch “negligible senes cence” (Finch, 1990, 1997). Thus, aging and longevity are of course correlated; however, this correlation is far from absolute. Note in addition that even many nonliv ing systems are able to age in the abovementioned sense (that is, the probability of their “death” increases with time); however, the nonliving systems are, as a rule, incapable of selfregeneration. A classic illustration of this statement is a wellknown picture from the wonder ful book by Alex Comfort (Comfort, 1964), describing the “aging” of glasses in a bar: the vessels of ground glass “age” with accumulation of defects, whereas the likeli hood of “death” for their thinwalled fellows is consid erably higher and remains constant to a complete “extinction” of the population. There is a standpoint (for example, see Campisi, 2005, 2007, 2008, 2011, 2013; Beausejour and Campisi, 2006; Campisi and d’Adda di Fagagna, 2007; Campisi and Yaswen, 2009) implying that the agedependent inhibition of cell proliferation in a multicellular organ ism and the decline in regeneration capacity of tissues and organs are provided by certain specialized mecha nisms that emerged in evolution and that decrease the risk for malignant transformation and thereby protect the organism from cancer. On the other hand, various macromolecular defects start to accumulate in senes cent cells that, on the contrary, elevate the probability for malignant transformation of these cells. Thus, according to the opinion of Campisi and other like minded persons, the restriction of cell proliferation is a doubleedged sword, which, on the one hand, decreases the probability for malignant tumor development in young age and, on the other, limits the lifespan due to accumulation of “spoiled” cells in old age. However, it remains unclear why normal human cells placed under in vitro conditions and thus having no mentioned “anticancer” barriers that function at the organismal level only NEVER undergo spontaneous malignant transformation. At least, this has hardly ever been observed in hundreds of laboratories involved in cultivation of such cells. It is possible to transform nor mal human fibroblasts only using special impacts, for RUSSIAN JOURNAL OF DEVELOPMENTAL BIOLOGY
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example, SV40 virus. The data of several papers report ing the cases of spontaneous transformation of normal human cells have been obtained with the cells isolated from the tissues and organs affected with cancer; there fore, the actual cleanness of these experiments causes certain doubts (Frosina, 2001). In addition, if to stick with the point of view of Campisi it is completely unclear how an organism such as the freshwater hydra escapes both aging and cancer, as it under certain conditions contains no postmitotic and senescent cells at all and under these conditions (excluding the need for sexual reproduction) can live almost indefinitely, possessing a tremendous regenera tive potential (a new organism can emerge from even 1/100 part of the old one) (Khokhlov, 1988; Martínez, 1998; Bosch, 2008; Estep, 2010; Martínez and Bridge, 2012). Apparently, hydra bluffs its way out of the whole thing as follows (Khokhlov, 1988). It is believed that the socalled interstitial cells (or, simply, icells) of hydra are able to both take part in budding and give rise to gametes. The hydra gametogenesis is a periodic process, after which it can again reproduce asexually. However, the gametogenesis lingers under certain conditions (change in environmental temperature), leading to depletion of icells, senility of individual, and death. The zone of continuous growth in hydra’s body is located under the hypostome. The newly formed cells move upwards (to the hypostome and tentacles) or downwards (to the formed buds and sexual glands) as well as along the body stalk to its foot, where necrotic masses are excreted through the aboral pore. Note that the sizes and specific individual features of the polyp remain constant. Thus, hydra is constantly being renewed, unencumbered by “senile” cells. According to the concept of aging that we adhere to (Khokhlov, 1988, 2010a, 2010b, 2013), the restricted proliferation of the cells forming organs and tissues in the majority of multicellular organisms results in accu mulation of various macromolecular damage in their bodies. The most important type of these defects is DNA damage (since a damage of the major template in many cases is unrepairable), which via chains of various events leads to an increase in the probability of death, that is, to aging of an individual (Gensler and Bernstein, 1981; Khokhlov, 1988, 2010b, 2013; Akifyev and Potap enko, 2001). The higher the rate of cell proliferation, the easier it is for the cells to escape accumulation of the damage at the level of cell population at the expense of a mere “dilution.” As for hydra, it succeeds owing to continuous cell renewal in retaining its viability at a constant level under certain conditions over almost indefinite time. It is noteworthy that the interest in the freshwater hydra as an example of a nonaging organism has again increased, which is demonstrated by several recent papers (Martínez, 1998; Bosch, 2008; Estep, 2010; Martínez and Bridge, 2012). Vol. 44
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There are good grounds to believe that the restriction of cell proliferation in an aging multicellular organism does not result from implementation of some special program of aging. It is likely that there is no such pro gram at all, while aging is a certain “byproduct” of the program of development (Austad, 1999, 2004; Holliday, 2007; Khokhlov, 2010a, 2013). Implementation of this program in higher organisms necessarily implies emer gence of cell populations with a very low or even zero proliferative activity, which is the particular factor that determines a limited capacity of the corresponding organs and tissues for regeneration. On the other hand, it is the presence of such populations of highly differen tiated cells, unable or poorly able to reproduce (neu rons, cardiomyocytes, hepatocytes), that provides for a normal functioning of higher animals and humans. Even regeneration of such organs with the help of stem (satellite) cells may interfere with the necessary links in elaborate systems. As has been earlier noticed (Khokhlov, 2010a), the program in a biological sense is a certain set of com mands; these commands are not given in response to a certain external impact being rather dependent only on the time scale. In this sense, apoptosis may be regarded as a programmed phenomenon only within the embry onic development, when its absence would just prevent development of a normal newborn organism. Indeed, there are many examples of the phenome non referred to as programmed death. However, these are examples of exactly programmed DEATH of an organism, which Skulachev (1997, 1999, 2011) named phenoptosis, rather than programmed AGING, that is, a programmed increase in the probability of death with age. I believe that this scheme for elimination of the already unnecessary individuals is too cumbersome and impractical for evolution to use this particular method for providing future prosperity of the species in general. It is known that the human aging, according to some data, starts as early as approximately in 15 years. How ever, this refers to human, a social being, which is pro tected from the adverse environmental impacts by the advances of civilization. As for wildlife, aging is, as a rule (note, as a rule, since there are some exceptions, such as elephants), unobservable, since almost all individuals die long before the beginning of the process. In addition, as I see it, even in the cases when evolution “notices” aging before the reproductive period comes to its end, it tries to SLOW DOWN this process and maximally increase the lifespan thereby extending both the dura tion of development and the period of fertility (it is what we actually observe over the last several million years). Presumably, INVENTION or ACCELERATION of aging (for example, with the help of a special program) is either unbeneficial or just senseless for evolution. The following argument may also favor the absence of evolutionarily created specialized aging program. In principle, any program may fail. In particular, we know many cases of impairments in the program of develop
ment, leading to either death of an embryo or delivery of abnormal offspring. However, I am not aware about any cases when the aging program (if it exists at all) in an aging individual has broken so as to make this individual “immortal.” Unfortunately, the recent considerable increase in interest in experimental gerontological research has led to a paradoxical situation: although the number of stud ies in this field is ever increasing, only a small part of them actually deals with aging mechanisms. As I see it, this situation is determined, among others, by the fol lowing circumstances. (1) As a rule, the classic definition of aging as a set of agerelated changes leading to an increase in the prob ability of death is ignored. (2) The focus in these studies is on an increase or a decrease in the lifespan; although, as is mentioned above, this had nothing to do with modification of aging (in particular, it is possible to successfully extend the lifespan for nonaging organisms; on the other hand, the very existence of aging does not necessarily suggest a short lifespan). (3) The animals with certain abnormalities (such as genetic diseases) are used as a control; thus, any favor able impact on the corresponding pathological pro cesses leads to an increase in lifespan. (4) Too much importance is attached to an increase or a decrease in the AVERAGE lifespan, which is in many respects determined by the factors that are in no way associated with aging. (5) The ever increasing number of gerontological experiments involves the model systems that give only indirect information about the aging mechanisms and whose interpretation, in many respects, depends on the basic concept shared by the corresponding researchers. In particular, this refers to the situation with the term “cell senescence.” Initially, this term was introduced to denote various adverse changes in normal cells RESULTING from depletion of their mitotic potential (Hayflick and Moorhead, 1961; Hayflick, 1965, 1979). On the contrary, this term now is ever more frequently used to denote the inhibition of cell proliferation (including cancer cell proliferation) accompanied by a certain cascade of intracellular reactions and caused by various DNAdamaging factors (Campisi, 2011, 2013; Sikora et al., 2011). (6) Finally, there is the issue that may be referred to as the “reductionism problem.” The overwhelming majority of gerontological theories that have appeared during the last decades reduced all the mechanisms underlying both “normal” and modified (accelerated or slowed down) aging of multicellular organisms to certain macromolecular alterations (it is not impor tant whether they are stochastic or programmed) in the constituent cells. This has given rise to numerous cytogerontological model systems for studying the “agerelated” changes in the cells freed from a “body
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level noise” associated with the functioning of the neurohumoral system. Such a reductionism in experimental gerontological studies (“everything is determined by adverse changes in individual cells”) has stimulated, in particular, emer gence of the Hayflick model as well as some other mod els used in our laboratory (stationary phase aging model, cellular kinetic model for testing of geroprotec tors and geropromoters, assessment of cell colony forming capacity, etc.). As for the abovementioned model based on the wellknown Hayflick phenomenon (in vitro aging), this model, as has been repeatedly mentioned (Olovnikov, 2005, 2007a, 2007b; Khokhlov, 2010a, 2010b, 2013; Khokhlov et al., 2012; Wei et al., 2012), is apparently not directly related to aging mechanisms. In other words, it is impossible to thoroughly explain why we age based on restricted mitotic potential of normal cells, which is almost never depleted in vivo. However, now, thanks to A.M. Olovnikov (Olovnikov, 1971, 1996), we at least know how this phenomenon is implemented in cells. Perhaps, if the human lifespan increased severalfold some cell populations in our body would exhaust their mitotic potential. Then, the “Hayflick limit” would lead to the “second wave” of aging; however, until now, this apparently does not take place. Nonetheless, it should be noted that some researchers (see, in particu lar, Mikhelson, 2001) still believe that telomere short ening in cells is the key aging mechanism. On the other hand, our model of stationary phase aging (accumulation of “agerelated” damage in cul tured cells whose proliferation is arrested by a certain method, best of all—via contact inhibition) implies a similarity between the processes taking place in a model system and whole body (Vilenchik et al., 1981; Khokhlov, 1988, 1992, 1998, 2003; Akimov and Khokhlov, 1998; Alinkina et al., 2012; Yablonskaya et al., 2013). In fact, such a similarity directly follows from the abovementioned theory, stating that the restriction of cell proliferation is the major mechanism for agedependent accumulation of macromolecular changes in cells of multicellular organisms (Khokhlov, 1988, 2010a, 2010b, 2013). Moreover, our recent stud ies have shown that the cells in the stationary growth phase actually become “to age according to Gompertz,” that is, the probability of their death increases with time in an exponential manner (Khokhlov, 2010b, 2013). Note that such experiments can be conducted with very diverse cells, including bacteria, yeasts (this is the most frequently used object for studying the station ary phase aging phenomenon), plant cells, mycoplas mas, etc., which provides for an evolutionary approach to analyzing the corresponding data. It is also important that, while the Hayflick model considerably hinders reproduction of experiments since the cells change from passage to passage (“you cannot step in the same river twice”), the model of stationary phase aging allows RUSSIAN JOURNAL OF DEVELOPMENTAL BIOLOGY
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us, in particular, to work with transformed (or normal but immortalized) cells, resolving the problem of repeated experiments (Khokhlov, 2012). Unfortunately, it currently looks as if even the data obtained using such models cannot be automatically extrapolated to the situation in the whole body (Khokhlov, 2010b, 2013). Our own studies of various geroprotectors and geropromoters with the help of the stationary phase aging model, cellular kinetic model, and estimation of cell colonyforming capacity have demonstrated that the studied factors in many cases fail to have a positive effect on the viability of cultured cells, although they extend the lifespan of experimen tal animals in a statistically significant manner as well as enhance human wellbeing and quality of life. This fact has suggested to us that the action of geroprotec tors in many cases manifests itself only at the level of the whole body and is not reduced to a mere improve ment of the viability of its cells. Presumably, a similar inference is true for many geropromoters. It is likely that the major players in the aging mech anisms in multicellular organisms are impairments in regulatory processes taking place at the neurohumoral level rather than a mere accumulation of macromolec ular defects in individual cells. It cannot be excluded that disturbance of such regulation is the particular reason for the frequently observed INCREASE in pro liferation intensity of some cell populations in old age leading to senile acromegaly and development of numerous benign tumors. Presumably, the quality of CONTROL over cells, organs, and tissues becomes poorer with age rather than the quality of the cells themselves, which leads to an increase in the death rate. In connection with the above, I would call my present scientific position antireductionism (Khokhlov, 2010b, 2013; Alinkina et al., 2012; Yablonskaya et al., 2013). Presumably, the aging of a multicellular organ ism is triggered at an organismal level, although it is implemented to a considerable degree at the level of individual cells. A special role in the process may be played by what we refer to as cell microenvironment (Conboy et al., 2005; Zahidov et al., 2010). Apparently, the mechanisms that determine devel opment and regeneration are very similar. In particular, the patterns on finger tips, determining fingerprints, appear due to the program of development but are very precisely (with 100% accuracy) maintained by the regeneration system. However, in the latter case, we should talk not about the program in the sense men tioned by me earlier, but on one of the systems that have arisen as a result of the implementation of the program of development and determined the proper functioning of an organism at a given level specified by this program. Humans have really “immortal” cells, namely, the germ line cells (Medvedev, 1981; Khokhlov, 1988), being analogues of the hydra icells. However, in this case, all the humankind over numerous generations represents this “hydra” and individuals should be Vol. 44
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Translated by G. Chirikova
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