DOI 10.1515/hmbci-2013-0030 Horm Mol Biol Clin Invest 2013; 16(1): 3–5
Mini Review Aria Baniahmad*
Why do we need to age? Abstract: A key question remains: why do multicellular organisms have a limited lifespan? The aging process is considered to be a decline of keeping the molecular, cellular and organ structure and interactions upright. It is hypothesized here that an evolutionary force has actively selected for limited lifespan and prior to that there is the process of aging. Many theories exist, including the endocrine theory of aging and reproduction-based aging. Here, a hypothesis is deduced for the driving force of the evolution of aging and lifespan limitation. Keywords: endocrine theory of aging; population; reproduction; senescence. *Corresponding author: Aria Baniahmad, Institute of Human Genetics, Jena University Hospital, Kollegiengasse 10, Jena, Germany, Phone: +49-3641-935524, Fax: +49-3641-934706, E-mail: [email protected]
Introduction It seems that most, if not all, multicellular organisms have a limited lifespan. The limitation is associated with an aging process that is thought to be caused by changes in organ function, leading to reduced body [1, 2]. This observation suggests that an evolutionary selection process could have evolved for aging and to limit lifespan. Thus, one of the key questions is why a lifespan limitation has evolved and in line with this why does an aging process exist that leads to lifespan limitation? Many theories on aging exist, which include the endocrine theory of aging, reproduction-based aging, telomere shortening, accumulation of mutation, caloric consumption associated with oxidative stress, free radicals and insulin signaling pathways, or loss of stem cells that eventually will lead to death [3, 4]. It is thought that aging may be a process of reducing the ability to keep all cellular and organismic pathways active at high levels. Diminishing the activity pathway capacities by age will result in reducing cellular and organ function by time and permits an higher entropy to occur in the organism.
On one hand, the diminished ability to keep pathways active in the elderly may be caused by reduced selection. However on the other hand, it may be considered that lifespan limitation is caused by an active selected process and that has been an evolved feature, which we call aging. In regard to this, it is hypothesized here that aging and the subsequent death of individuals is beneficial for the population and has been positively selected during evolution. Thus, is there a biological selection to explain aging and lifespan limitation as an advantage for the population?
Reproduction, aging and lifespan The definition of aging is not easy. An organism changes during embryonic development, as a juvenile and also in adulthood. Comparing the development of different organisms, including humans, many changes are apparent between the young and elderly. The most common change in elderly people is reduced organ activity. Accordingly, the reproduction capability is also reduced in elderly people. In line with this the endocrine theory of aging is based on the age-dependent reduction of a series of key hormones that regulate the reproduction [5]. In general, aging may be considered and defined as a decline of body function at the last period of life. Therefore, this suggests that the endocrine system that permits not only fertility but also communication between different organs in our body plays an important part in this aging process. The theory of telomere shortening is accompanied with telomerase activity and implies that shorter telomeres lead to lifespan limitation. Indeed shorter telomeres lead to the induction of a cellular stress response program and reduced cell division, which also applies to stem cells [6]. However, whether longer telomeres will lead to a longer life span has not yet been shown. Notably, some mice strains have longer telomeres compared to humans but their lifespan is only a fraction of the length. This suggests that telomere length by itself may contribute but may not be the single pivotal and decisive biological clock of limiting lifespan. The mutations theory suggests an accumulation of mutations in somatic cells over time. An increase
4 Baniahmad: Why do we need to age? in mutations will lead to an increase in aberrant gene expression that, through accumulation over time, leads to reduced function of pathways and thus provides one basis of aging. This theory has its origins in the analysis of progeria syndromes where the cells of these patients exhibit reduced DNA stability. Many studies have revealed an accumulation of genomic of mitochondrial mutations in the elderly. However, whether this causes the lifespan limitation of mammals is unclear. An interesting theory of aging is based on the role of metabolic rate, linked to food uptake, insulin pathway, sirtuins, mTOR and ROS production. The role of the insulin signaling to regulate life span has been shown to be an important pathway in many organisms including Caenorhabditis elegans, Drosophila, yeast and mammals [7–9]. Hereby, organisms exhibit longer life spans when the insulin hormone pathway is reduced or mutated. Accordingly, reports strongly suggest that caloric restriction leads to lifespan extension. However, caloric restriction and an increased lifespan may be associated with reduced reproductive capacity. Thus, lifespan limitation and the aging process are interlinked and highly conserved biological processes. This implies the existence of a natural selection process that is imposed. Concerning population theories it is suggested that any species with successful progenies have an advantage and will survive. Therefore, a successful reproduction process, as well as for the progenies, is an essential part of the theory. The endocrine theory of aging is based on the agedependent reduction of a series of hormones, including growth hormone, steroids such as de-hydro-epi-androsterone (DHEA), testosterone, estrogens and progestins as well as thyroid hormones, melatonin and others [5, 10]; and discussed in this issue by Escames et al. [11]. Also some links between reproduction, lifespan and hormone are known in non-mammals [12, 13]. Most of these hormones mentioned above play an essential role in reproduction. Noteworthy, so far to our knowledge in humans, hormone replacement has not been measured to lead to lifespan extension. One reason could be the over-imposed effects of deaths caused by cancer and the cardiovascular system in elderly.
The evolution of aging and lifespan limitation: a hypothesis With an evolutionary selection for aging and lifespan, it is considered that after the reproduction phase a selection process on the elderly cannot or will only poorly occur.
This may be true for species that do not care for their offsprings. However, for those species that care for their progeny, and where it will benefit the progeny to reproduce successfully, a rapid aging and life limitation shortly after reproduction is not beneficial. The central question remains: why is there no unlimited lifespan for most multicellular organisms? It is discussed here that limiting lifespan may have a long-term advantage for the population and that an unlimited lifespan is disadvantageous. Assuming hypothetically that organisms would not age and have a potential for unlimited life span, this will presumably be associated with a high degree and a high potential for renewing body functions. In this hypothetical model, the death of one individual from the population will only occur in a stochastic manner, such as in an accident. This kind of decline of the population would correspond mathematically to a graph that represents the description of half-life time processes, such as of radioactive material for which at a specific time period half of the molecules disintegrate. Thus, to ensure stability of the size of a population only the stochastic decline of a population must be counteracted solely by replacing the number of lost individuals. Consequently, to ensure a relatively constant number of individuals within a population, it is required to produce a number of progenies that equals roughly the number of lost individuals of a given population. In line with that, the reproducibility and reproductive capacity would be only high for those species that exhibit a considerable loss of individuals. Whereas those populations who have strongly reduced their losses of individuals will sooner or later lose evolutionary selection for high reproduction capacity and will exhibit a lower reproductive rate. Thus, the hypothesis is that a selection force with natural reproduction and fertility as the bases of the survival of the population will not be required. Accordingly, no evolutionary selection is put on a hypothetical ‘ideal’ population that does not lose individuals. In such a population the selection on reproduction capacity will be reduced and concordantly also the selection for high fertility will be lost, as no significant reproduction is necessary to maintain the population size. Thus, one could imagine that under this ‘ideal’ situation a decline in the reproductive capacity of such a population does no harm. The longer this ‘ideal’ population exhibits no losses, a reduced fertility will not be selected against and the longer such a population exists, the higher the decline of reproductive capacity will be. In general, in evolutionary views it is easier to lose a biological function compared to gain of function. Therefore, towards the development of such an ‘ideal’ population without sign of aging and death, a reduced reproductive capacity will
Baniahmad: Why do we need to age? 5
be inherited into next generations without short-term harm for the survival of the population. Eventually, over time, in that population a further reduction or even a loss of reproductive capacity will expand among progenies. That evolutionary development is, however, a very critical development that could lead to a population crisis. The decline or even absence of a selection force for reproduction, by change of the environment would, on long-term view, be highly hazardous for such a population. Thus, an ‘ideal’ population that exhibits no aging and no lifespan limitation sooner or later will have a strongly reduced reproductive capacity. The danger hereby is that, with a change of the environment leading to many deaths of individuals, the recovery of the population size will be much more difficult compared to a population that possesses a high reproductive capacity. These hypothetical scenarios clearly suggest that a selection force for aging and lifespan limitation is essential to ensure the survival of a population.
Therefore, considering those conditions that may lead to reducing reproductive capacity by a non-aging population is contraindicative for a species. Thus, the evolution of populations requires individuals that select their reproductive capacity. Therefore aging and lifespan limitation is beneficial for populations to enforce and select for aging and death. Thus, from an evolutionarily stand point only those populations survive for which the individuals show the phenomenon of aging and organismic death. An important issue is however, to minimize the ageassociated diseases. As the age-dependent decline of hormones can lead to reduced body function the key question is whether age-dependent hormone-associated decline in body function can be minimized. This special issue of HMBCI tries to shed some light into some of the aspects of hormones and aging. Received June 14, 2013; accepted July 18, 2013; previously published online August 20, 2013
References 1. Hayflick L. Biological aging is no longer an unsolved problem. Ann NY Acad Sci 2007;1100:1–13. 2. Hayflick L. Living forever and dying in the attempt. Exp Gerontol 2003;38:1231–41. 3. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 2013;153:1194–217. 4. Tosato M, Zamboni V, Ferrini A, Cesari M. The aging process and potential interventions to extend life expectancy. Clin Interv Aging 2007;2:401–12. 5. Zouboulis CC, Makrantonaki E. Hormonal therapy of intrinsic aging. Rejuvenation Res 2012;15:302–12. 6. Campisi J, Yaswen P. Aging and cancer cell biology 2009. Aging Cell 2009;8:221–5. 7. O’ Neill C. PI3-kinase/Akt/mTOR signaling: Impaired on/off switches in aging, cognitive decline and Alzheimer’s disease. Exp Gerontol 2013;48:647–53. 8. Tucci P. Caloric restriction: is mammalian life extension linked to p53? Aging 2012;4:525–34.
9. Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 2012;13: 225–38. 10. Makrantonaki E, Schonknecht P, Hossini AM, Kaiser E, Katsouli MM, Adjaye J, Schroder J, Zouboulis CC. Skin and brain age together: The role of hormones in the ageing process. Exp Gerontol 2010;45:801–13. 11. Escames G, Diaz-Casado ME, Doerrier C, Luna-Sanchez M, Lopez CL, Acuna-Castroviejo D. Early gender differences in the redox status of brain mitochondria with age. Effects of melatonin therapy. Horm Mol Biol Clin Invest 2013;16:91–100. 12. Gáliková M, Klepsatel P, Senti G, Flatt T. Steroid hormone regulation of C. elegans and Drosophila aging and life history. Exp Gerontol 2011;46:141–7. 13. Kenyon C. A pathway that links reproductive status to lifespan in Caenorhabditis elegans. Ann NY Acad Sci 2010;1204: 156–62.
Copyright of Hormone Molecular Biology & Clinical Investigation is the property of De Gruyter and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Mini Review Aria Baniahmad*
Why do we need to age? Abstract: A key question remains: why do multicellular organisms have a limited lifespan? The aging process is considered to be a decline of keeping the molecular, cellular and organ structure and interactions upright. It is hypothesized here that an evolutionary force has actively selected for limited lifespan and prior to that there is the process of aging. Many theories exist, including the endocrine theory of aging and reproduction-based aging. Here, a hypothesis is deduced for the driving force of the evolution of aging and lifespan limitation. Keywords: endocrine theory of aging; population; reproduction; senescence. *Corresponding author: Aria Baniahmad, Institute of Human Genetics, Jena University Hospital, Kollegiengasse 10, Jena, Germany, Phone: +49-3641-935524, Fax: +49-3641-934706, E-mail: [email protected]
Introduction It seems that most, if not all, multicellular organisms have a limited lifespan. The limitation is associated with an aging process that is thought to be caused by changes in organ function, leading to reduced body [1, 2]. This observation suggests that an evolutionary selection process could have evolved for aging and to limit lifespan. Thus, one of the key questions is why a lifespan limitation has evolved and in line with this why does an aging process exist that leads to lifespan limitation? Many theories on aging exist, which include the endocrine theory of aging, reproduction-based aging, telomere shortening, accumulation of mutation, caloric consumption associated with oxidative stress, free radicals and insulin signaling pathways, or loss of stem cells that eventually will lead to death [3, 4]. It is thought that aging may be a process of reducing the ability to keep all cellular and organismic pathways active at high levels. Diminishing the activity pathway capacities by age will result in reducing cellular and organ function by time and permits an higher entropy to occur in the organism.
On one hand, the diminished ability to keep pathways active in the elderly may be caused by reduced selection. However on the other hand, it may be considered that lifespan limitation is caused by an active selected process and that has been an evolved feature, which we call aging. In regard to this, it is hypothesized here that aging and the subsequent death of individuals is beneficial for the population and has been positively selected during evolution. Thus, is there a biological selection to explain aging and lifespan limitation as an advantage for the population?
Reproduction, aging and lifespan The definition of aging is not easy. An organism changes during embryonic development, as a juvenile and also in adulthood. Comparing the development of different organisms, including humans, many changes are apparent between the young and elderly. The most common change in elderly people is reduced organ activity. Accordingly, the reproduction capability is also reduced in elderly people. In line with this the endocrine theory of aging is based on the age-dependent reduction of a series of key hormones that regulate the reproduction [5]. In general, aging may be considered and defined as a decline of body function at the last period of life. Therefore, this suggests that the endocrine system that permits not only fertility but also communication between different organs in our body plays an important part in this aging process. The theory of telomere shortening is accompanied with telomerase activity and implies that shorter telomeres lead to lifespan limitation. Indeed shorter telomeres lead to the induction of a cellular stress response program and reduced cell division, which also applies to stem cells [6]. However, whether longer telomeres will lead to a longer life span has not yet been shown. Notably, some mice strains have longer telomeres compared to humans but their lifespan is only a fraction of the length. This suggests that telomere length by itself may contribute but may not be the single pivotal and decisive biological clock of limiting lifespan. The mutations theory suggests an accumulation of mutations in somatic cells over time. An increase
4 Baniahmad: Why do we need to age? in mutations will lead to an increase in aberrant gene expression that, through accumulation over time, leads to reduced function of pathways and thus provides one basis of aging. This theory has its origins in the analysis of progeria syndromes where the cells of these patients exhibit reduced DNA stability. Many studies have revealed an accumulation of genomic of mitochondrial mutations in the elderly. However, whether this causes the lifespan limitation of mammals is unclear. An interesting theory of aging is based on the role of metabolic rate, linked to food uptake, insulin pathway, sirtuins, mTOR and ROS production. The role of the insulin signaling to regulate life span has been shown to be an important pathway in many organisms including Caenorhabditis elegans, Drosophila, yeast and mammals [7–9]. Hereby, organisms exhibit longer life spans when the insulin hormone pathway is reduced or mutated. Accordingly, reports strongly suggest that caloric restriction leads to lifespan extension. However, caloric restriction and an increased lifespan may be associated with reduced reproductive capacity. Thus, lifespan limitation and the aging process are interlinked and highly conserved biological processes. This implies the existence of a natural selection process that is imposed. Concerning population theories it is suggested that any species with successful progenies have an advantage and will survive. Therefore, a successful reproduction process, as well as for the progenies, is an essential part of the theory. The endocrine theory of aging is based on the agedependent reduction of a series of hormones, including growth hormone, steroids such as de-hydro-epi-androsterone (DHEA), testosterone, estrogens and progestins as well as thyroid hormones, melatonin and others [5, 10]; and discussed in this issue by Escames et al. [11]. Also some links between reproduction, lifespan and hormone are known in non-mammals [12, 13]. Most of these hormones mentioned above play an essential role in reproduction. Noteworthy, so far to our knowledge in humans, hormone replacement has not been measured to lead to lifespan extension. One reason could be the over-imposed effects of deaths caused by cancer and the cardiovascular system in elderly.
The evolution of aging and lifespan limitation: a hypothesis With an evolutionary selection for aging and lifespan, it is considered that after the reproduction phase a selection process on the elderly cannot or will only poorly occur.
This may be true for species that do not care for their offsprings. However, for those species that care for their progeny, and where it will benefit the progeny to reproduce successfully, a rapid aging and life limitation shortly after reproduction is not beneficial. The central question remains: why is there no unlimited lifespan for most multicellular organisms? It is discussed here that limiting lifespan may have a long-term advantage for the population and that an unlimited lifespan is disadvantageous. Assuming hypothetically that organisms would not age and have a potential for unlimited life span, this will presumably be associated with a high degree and a high potential for renewing body functions. In this hypothetical model, the death of one individual from the population will only occur in a stochastic manner, such as in an accident. This kind of decline of the population would correspond mathematically to a graph that represents the description of half-life time processes, such as of radioactive material for which at a specific time period half of the molecules disintegrate. Thus, to ensure stability of the size of a population only the stochastic decline of a population must be counteracted solely by replacing the number of lost individuals. Consequently, to ensure a relatively constant number of individuals within a population, it is required to produce a number of progenies that equals roughly the number of lost individuals of a given population. In line with that, the reproducibility and reproductive capacity would be only high for those species that exhibit a considerable loss of individuals. Whereas those populations who have strongly reduced their losses of individuals will sooner or later lose evolutionary selection for high reproduction capacity and will exhibit a lower reproductive rate. Thus, the hypothesis is that a selection force with natural reproduction and fertility as the bases of the survival of the population will not be required. Accordingly, no evolutionary selection is put on a hypothetical ‘ideal’ population that does not lose individuals. In such a population the selection on reproduction capacity will be reduced and concordantly also the selection for high fertility will be lost, as no significant reproduction is necessary to maintain the population size. Thus, one could imagine that under this ‘ideal’ situation a decline in the reproductive capacity of such a population does no harm. The longer this ‘ideal’ population exhibits no losses, a reduced fertility will not be selected against and the longer such a population exists, the higher the decline of reproductive capacity will be. In general, in evolutionary views it is easier to lose a biological function compared to gain of function. Therefore, towards the development of such an ‘ideal’ population without sign of aging and death, a reduced reproductive capacity will
Baniahmad: Why do we need to age? 5
be inherited into next generations without short-term harm for the survival of the population. Eventually, over time, in that population a further reduction or even a loss of reproductive capacity will expand among progenies. That evolutionary development is, however, a very critical development that could lead to a population crisis. The decline or even absence of a selection force for reproduction, by change of the environment would, on long-term view, be highly hazardous for such a population. Thus, an ‘ideal’ population that exhibits no aging and no lifespan limitation sooner or later will have a strongly reduced reproductive capacity. The danger hereby is that, with a change of the environment leading to many deaths of individuals, the recovery of the population size will be much more difficult compared to a population that possesses a high reproductive capacity. These hypothetical scenarios clearly suggest that a selection force for aging and lifespan limitation is essential to ensure the survival of a population.
Therefore, considering those conditions that may lead to reducing reproductive capacity by a non-aging population is contraindicative for a species. Thus, the evolution of populations requires individuals that select their reproductive capacity. Therefore aging and lifespan limitation is beneficial for populations to enforce and select for aging and death. Thus, from an evolutionarily stand point only those populations survive for which the individuals show the phenomenon of aging and organismic death. An important issue is however, to minimize the ageassociated diseases. As the age-dependent decline of hormones can lead to reduced body function the key question is whether age-dependent hormone-associated decline in body function can be minimized. This special issue of HMBCI tries to shed some light into some of the aspects of hormones and aging. Received June 14, 2013; accepted July 18, 2013; previously published online August 20, 2013
References 1. Hayflick L. Biological aging is no longer an unsolved problem. Ann NY Acad Sci 2007;1100:1–13. 2. Hayflick L. Living forever and dying in the attempt. Exp Gerontol 2003;38:1231–41. 3. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 2013;153:1194–217. 4. Tosato M, Zamboni V, Ferrini A, Cesari M. The aging process and potential interventions to extend life expectancy. Clin Interv Aging 2007;2:401–12. 5. Zouboulis CC, Makrantonaki E. Hormonal therapy of intrinsic aging. Rejuvenation Res 2012;15:302–12. 6. Campisi J, Yaswen P. Aging and cancer cell biology 2009. Aging Cell 2009;8:221–5. 7. O’ Neill C. PI3-kinase/Akt/mTOR signaling: Impaired on/off switches in aging, cognitive decline and Alzheimer’s disease. Exp Gerontol 2013;48:647–53. 8. Tucci P. Caloric restriction: is mammalian life extension linked to p53? Aging 2012;4:525–34.
9. Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 2012;13: 225–38. 10. Makrantonaki E, Schonknecht P, Hossini AM, Kaiser E, Katsouli MM, Adjaye J, Schroder J, Zouboulis CC. Skin and brain age together: The role of hormones in the ageing process. Exp Gerontol 2010;45:801–13. 11. Escames G, Diaz-Casado ME, Doerrier C, Luna-Sanchez M, Lopez CL, Acuna-Castroviejo D. Early gender differences in the redox status of brain mitochondria with age. Effects of melatonin therapy. Horm Mol Biol Clin Invest 2013;16:91–100. 12. Gáliková M, Klepsatel P, Senti G, Flatt T. Steroid hormone regulation of C. elegans and Drosophila aging and life history. Exp Gerontol 2011;46:141–7. 13. Kenyon C. A pathway that links reproductive status to lifespan in Caenorhabditis elegans. Ann NY Acad Sci 2010;1204: 156–62.
Copyright of Hormone Molecular Biology & Clinical Investigation is the property of De Gruyter and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
