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The free radical theory of frailty: Mechanisms and opportunities for interventions to promote successful aging
Accepted Manuscript The free radical theory of frailty: Mechanisms and opportunities for interventions to promote successful aging Jose Viña PII:
S0891-5849(18)32651-0
DOI:
https://doi.org/10.1016/j.freeradbiomed.2019.01.045
Reference:
FRB 14143
To appear in:
Free Radical Biology and Medicine
Received Date: 30 December 2018 Revised Date:
30 January 2019
Accepted Date: 31 January 2019
Please cite this article as: J. Viña, The free radical theory of frailty: Mechanisms and opportunities for interventions to promote successful aging, Free Radical Biology and Medicine (2019), doi: https:// doi.org/10.1016/j.freeradbiomed.2019.01.045. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Adaptation to exercise, nutrition or micronutrient supplements
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Oxidative damage vs oxidative stress in the pathophysiology of frailty
Mitochondrial damage, pollution radiation, unsucesful aging
ACCEPTED MANUSCRIPT INVITED MINI REVIEW FREE RADICAL BIOLOGY AND MEDICINE The free radical theory of frailty: mechanisms interventions to promote successful aging.
and
opportunities
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Jose Viña, MD, PhD
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Affiliation: Freshage Research Group-Department of Physiology, Faculty of Medicine, University of Valencia, CIBERFES and INCLIVA, Avenida Blasco Ibañez nº 15, 46010, Valencia, Spain. Address correspondence to: Dr. Jose Vina
Av. Blasco Ibañez, 15, 46010, Valencia, Spain.
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Department of Physiology. Faculty of Medicine. University of Valencia.
Email: [email protected]
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Phone: (34) 96 386 46 50; Fax: (34) 96 386 46 42
Conflict of interest: The author declares that no conflict of interest exists.
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Acknowledgements: Work from the author’s laboratory was supported by the following grants: Instituto de Salud Carlos III and co-funded by FEDER [grant number PIE15/00013], SAF2016-75508-R from the Spanish Ministry of Education and Science (MEC), CB16/10/00435 (CIBERFES), EU Funded FRAILOMIC-HEALTH.2012.2.1.1-2 and ADVANTAGE-724099 Join Action (HPJA) 3rd EU Health Programme.
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The author thanks Mrs. Marilyn Noyes for her kind help in reviewing the manuscript and Drs Gomez-Cabrera and Borras for their help with this paper.
ACCEPTED MANUSCRIPT ABSTRACT
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The free radical theory of ageing has provided a framework of research into ageing based on Harman’s idea that ageing was caused by damage produced by free radicals. However, several experiments have cast doubts on the general validity of the theory. The postulation of the free radical theory of frailty came from two basic facts: first that radicals not only act as damaging molecules, but also as signals to control cell function and second that on many occasions oxidative damage does not correlate with chronological but rather with unsuccessful ageing. Frailty is a geriatric concept by which an older person shows a lack of the feeling of wellbeing, unintentional weight loss, a relatively low grip strength, lowering the speed of walking, and difficulties to stand. If left untreated, frailty progresses to disability. Many interventions that prevent oxidative damage to cells do not affect longevity but have a clear effect on the prevention of frailty and its transition to disability. Clinical trials have shown that exercise programmes do not promote longevity but delay the onset of frailty. Experiments and mechanisms to support this idea are described.
ACCEPTED MANUSCRIPT 1.-The free radical theory of aging: relevance and the debate on its validity. Pros and cons of the free radical theory of aging.
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Postulating theories to understand ageing has been a major undertaking of biogerontologists for over a century. Of the more than 300 theories of ageing that we found in a review of the literature in 2007 [1], the free radical theory was one of the most interesting because it provided not only a mechanism to understand damage associated with ageing (this, according to the theory, was damage caused by oxygen radicals), but it also provided room for intervention as antioxidants could be administered to delay or prevent the damage caused by oxidants.
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Interest in oxidative free radicals was greatly boosted by the finding of Rebecca Gershman that radiation-induced injury could be attributed to the effects of oxygen radicals. This was published back in 1955 [2]. One year later, in a classic paper, Denham Harman proposed his free radical theory of ageing that stated that “ageing and degenerative diseases associated with it are attributed basically to the deleterious side attacks of free radicals on cell constituents and on the connective tissues” [3]. This is literally Harman’s formulation of the free radical theory of ageing where he, with great hindsight, proposed that damage associated with ageing or interestingly associated with degenerative diseases that come with age, could be due to the effects of free radicals on cell constituents. The obvious corollary to this theory was that the administration of antioxidants would be good for your health as it would prevent damage associated with these radicals that leads to ageing and to degenerative diseases. A great boost to the general idea that disease could be associated with oxidation and that antioxidants would be beneficial came from the ideas of a genius of the stature of Linus Pauling. In his widely read book “Vitamin C, the Common Cold and the Flu” [4]. Linus Pauling proposed that administration of high doses (on some occasions enormous doses) of vitamin C could lead to an efficacious prevention of the common cold and of the flu, a disease that causes thousands of deaths every year, especially among the older population.
This was how the scene was around the mid-70s and twenty-five years were to pass before critical experiments could be performed that disproved the general validity of Harman’s free radical theory of ageing.
But around the turn of the century, two critical ideas came to the forefront of radical research and changed our interpretation of how free radicals interact with living matter. The first was that free radicals could act as signals [5, 6] and not just as damaging molecules. Radicals were in the cell to contribute to the wonderfully complex web of signals that allow different metabolic pathways to act in a smooth synergistic way. The second idea was that it is better to promote endogenous antioxidant enzymes, such as superoxide dismutases,
ACCEPTED MANUSCRIPT catalase, glutathione peroxidases, etc. rather than giving exogenous antioxidant molecules, usually low molecular weight, such as vitamin C or E [7]. Thus, the idea of a normal level of oxygen species having a function in regulating cell metabolism, and in general cell life, became entrenched in the minds of researchers and led to critical experiments to try and disprove [8] the free radical theory of ageing [3].
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Thus a number of experiments became available showing that the free radical theory of ageing was still valid, but a number of others clearly showed that this was not the case. I shall now refer to some of them showing how difficult the situation was for researchers in the field because of the discrepancies regarding the validity of the free radical theory of ageing. Moosmann and Behl [9] in 2008 published results that literally “provided distinct support for the free radical theory of ageing”. But, on the other hand, the laboratory of Arlan Richardson in a review published in 2009 described that “data calls into serious question the hypothesis that alterations in oxidative damage play a role in the longevity of mice” [10]. The actual title of the paper was “Is the oxidative stress theory of ageing dead?”. Then a paper in Experimental Gerontology by an international group that included researchers of the level of Tomas Prolla, Gustavo Barja, or Christiaan Leeuwenburg provided results that gave full support to the mitochondrial free radical theory of ageing [11]. Many other papers were published with some in favour, but some were clearly showing that the free radical theory of ageing was difficult to reconcile with the available evidence, at least as postulated by Harman. Importantly, the laboratory of Hekimi reported that superoxide signals triggers increase longevity in C. elegans thus concluding that the findings were not consistent with the free radical theory of ageing [12]. But, on the other hand, in a review paper published in 2011 in Nature, Kelly placed reactive oxygen species (as he named them) precisely in the middle of the causes of damage associated with ageing [13]. Many other reports on experiments against the free radical theory of ageing could be mentioned here, but I shall only mention work from our own laboratory in which the main corollary, i.e. that antioxidants are advantageous is disproved. By 2008, we observed that feeding rats with high doses of vitamin C did prevent the adaptations of muscle to physical training [14]. The idea that radicals associated with exercise could trigger mitochondriogenesis had initially been put forward by Davies, Quintanilha, Brooks and Packer in their classic 1982 paper on physical exercise [15]. What we did was to show that training in both rats and humans was greatly hindered by administration of high doses of vitamin C and the explanation was that not only mitochondrial biogenesis was impaired, but that the increased expression of antioxidant enzymes could also be impaired by administration of antioxidants. One year later, i.e. in 2009, Michael Ristow and colleagues showed that antioxidant administration not only hinders the improvements in physical performance associated with exercise, but it also diminishes the improvements in health status associated with exercise [16].
ACCEPTED MANUSCRIPT To sum up we, and others, reported facts that go firmly against the idea that oxidation associated with exercise is always bad and that one should not take antioxidants without critical hesitation.
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The experiments and thoughts we have just reported here indicate that the general idea of the free radical theory of ageing useful as it was and is, had to be revised to cope with the new evidence showing that oxygen radicals were not always bad for your health. 2.- Definition of frailty, disability and intrinsic capacity
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One of the major new concepts in geriatrics in the last two decades is the identification of the frailty phenotype. This was put forward by researchers at Johns Hopkins School of Medicine in Baltimore led by Linda Fried and Jeremy Walston [17]. The phenotype of the frail old individual has been described in many publications, symposia have been devoted to it, and even EU projects have been granted to reach a definition of frailty [18].. Frailty is a geriatric syndrome by which an older person displays increased vulnerability to minor stresses. A frail person feels a lack of well-being, unintentional weight loss, a relatively low grip strength, slow walking speed, and difficulties to stand. If left untreated, frailty progresses to disability
If a young person shows some of the traits of frailty that I have just mentioned, then it is not a case of frailty but rather a specific disease
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The physiology behind this lack of energy is probably the fact that frail persons do not have the capacity to react against stresses that the vigorous ones have. The most important corollary of the frailty status is that eventually it leads to disability. Figure 1, top panel shows the predictions of the European Union at its meeting in Lisbon in 2000 that by the year 2020 approximately 30% of the European population over 65 will be frail, but that the situation worsens rapidly and that by 2050, half of the European population over 65 will be frail or even disabled. This indicates that the personal, medical, social and economic weight of disability is going to become, or has already become, a major problem and an opportunity for society today. The estimated cost of disability is shown in the lower panel of Figure 1 lower panel. A robust old person requires only 900 € per year whereas a dependent one requires more than 14000 €, in increase of more than 16 fold. The importance of frailty in the clinical scenario has already been described [19]. The idea of frailty as leading to disability, has prompted much reflection in the scientific community and recently the World Health Organization (WHO) has put forward the idea of the intrinsic capacity. In essence, intrinsic capacity seems to be the opposite of frailty, i.e., if a person has high intrinsic capacity then it is unlikely that he/she will become frail. In fact, the WHO defines intrinsic capacity as “the composite of all physical and mental capacities that an individual can draw upon at any point of their life”. Healthy ageing was defined as “the process of developing and maintaining functional ability that enables wellbeing in older age”. The claim is that healthy ageing depends finally on the
ACCEPTED MANUSCRIPT intrinsic capacity of an individual and the interaction of this individual with his/her environment.
A most important point is that the individual variations of intrinsic capacity in general terms increase with age. Thus, there will be more differences between two individuals in older age than in younger age in terms of intrinsic capacity.
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This has not been defined in clear clinical terms as has frailty, but it helps to shift attention from public health measures of health promotion, such as vaccination or systematic search for age-associated. Needless to say, the newer concept of intrinsic capacity immediately brings forward the idea that each individual should try and promote their own intrinsic capacity, certainly under the close scrutiny of healthcare professionals [20]. Programmes of physical exercise, that must be personalised (in the framework of stratified, i.e. not just adjusted for one person, but for groups of persons with similar intrinsic capacity) must also be multicomponent taking into account at least three approaches (aerobic, strength and equilibrium types of exercise) and must be social because experience tells us that the adherence of exercise when practised in a social context is much higher than when practised individually. As I shall describe later on in this paper, free radicals are much more involved in the process of developing frailty than in ageing itself
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3.- Formulation of the free radical theory of frailty
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The basic facts that we considered to propose as a hypothesis that oxidative stress is related to frailty and not to ageing are the following: In the first place, ageing is not always associated with oxidative stress (as described above). In second term ageing is often associated with frailty, and is also often associated with oxidative damage. Finally, we observed both in animals and in humans, that ageing itself is not associated with oxidative damage but that only unsuccessful ageing is associated with oxidation. Further confirmation of this hypothesis came from work in centenarians who enjoy a long, productive and in many cases disease-free old age and whose oxidative stress is in many cases lower than that we observe in octogenarians [21]. The hypothesis, therefore, was that ageing could be dissociated from oxidative damage and that only unsuccessful ageing i.e. frailty, could be associated with oxidative damage. Figure 2 top panel graphically describes the idea that contolled oxidative stress leads to successful aging and that only uncontrolled stress leads to damage. Thus, we proposed in this Journal our free radical theory of frailty [22] . This theory states that frailty is associated with oxidative damage to tissues and to macromolecules. Experiments must be devised to try and disprove the theory [8]. Thus, we and others set out to try and disprove this free radical theory of frailty.
ACCEPTED MANUSCRIPT 4.- Testing the free radical theory of frailty: animal and human studies
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The free radical theory of frailty has been tested in both experimental animals and humans. The general approach to the experimental animal has been twosided: from one side the development of animals that were either suffering high oxidative stress or suffering low oxidative stress could result respectively in increased frailty or decreased frailty, but without changes in longevity. Another approach has been to supplement animals with, for instance, nicotinamide riboside resulting in alterations in oxidative stress that did not lead to changes in longevity, but that affect what researchers termed as “healthspan”.
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We would like to mention here that in many biological papers, researchers refer to healthspan whereas in the clinical scenario, clinicians tend to refer more to frailty and eventual disability rather to the loss of healthspan. After pondering the observations of both experimental researchers and clinicians, I tend to conclude that both terms can be used for our purposes at least, interchangeably. In any case, I shall go on using the term frailty for the purposes of this review paper. The tests to the theory have also provided mechanisms that we can use to approach the problem at hand. This is the emphasis of this paper: that understanding mechanisms can lead to us to better refine the free radical theory of frailty and to better understand the concept of healthspan which can also be correlated with that of intrinsic capacity.
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As stated above, two different molecular approaches have been used to tackle the problem of the relationship between ageing, frailty and oxidative stress. In the first instance, an excellent group of researchers from both the USA (Arlan Richardson and his group) as well as from the UK (Malcolm Jackson and his group) generated a superoxide-dismutase-deficient mouse (SOD-/-) [23]. As expected, this animal suffered from high oxidative stress and high oxidative damage because a critical enzyme to detoxify superoxide was absent. The animal, however, did not live less than the controls, but most interestingly, the quality of life, i.e. the healthspan was considerably decreased and the onset of frailty accelerated. This was a most important test of the free radical theory of frailty: increasing oxidative stress by molecular means does not lead to decreased longevity but rather to increased frailty. But there is another approach that could be used that is almost the “other side of the coin” of the experiments we have just described. And this was carried out by our laboratory in cooperation with that of Dr Manuel Serrano from Barcelona. Our aim was to generate a mouse that overexpresses glucose 6 phosphate dehydrogenase (G6PD) [24]. G6PD is a critical enzyme in the generation of reducing equivalents in the form of NADP. In my opinion, it is most important because it provides (from glucose) a continuous flow of reducing equivalents to counteract the continuous flow of oxidising equivalents that come essentially from oxygen. A complete network of antioxidant mechanisms exists between
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the NADPH and superoxide, but the initial event in terms of pro-oxidation comes from oxygen whereas the initial event in anti-oxidation comes from glucose through G6PD. We thus generated the G6PD overexpressing mouse and observed that it does confer a significant protection against oxidative stress, a remarkable increase in resistance against oxidation by agents such as diamide, but no significant changes in longevity. Only a relatively minor change in longevity only in females could be observed. But we found that this animal is seriously protected against metabolic stresses.
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Unpublished experiments from our laboratory show that the G6PD overexpressing mouse displays a delay in the onset of frailty. We have achieved this by using a new frailty index that we have developed that is called “Valencia index for frailty in experimental animals” [25]. This is an index that we developed based on the criteria that have been used in the clinical setting, especially derived from the work of Linda Fried and co-workers [17]. The animals that were expressing G6PD display a clear delay in the onset of frailty as determined by our Valencia index of frailty.
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So animals that suffer high oxidative stress (SOD-/-) or low oxidative stress (G6PD) live the same as their controls: longevity is dissociated from oxidative stress, but in both cases the animals that have higher oxidative stress show earlier signs of frailty and those that have lower oxidative stress display an increased healthspan and delay in frailty.
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The validity of the free radical theory of frailty has also come from experiments in which the animals were treated with oral supplements rather than with molecular alterations of the genome expression. Experiments in which nutritional supplementation increases healthspan, but not lifespan, have been performed in several laboratories. I shall discuss here a critical paper from the de Cabo laboratory [26]. In this paper, the authors supplemented mice with nicotinamide riboside and they observed that the longevity of both treated and untreated was unchanged. However, measures of parameters that are usually considered part of any frailty index (as is usual in biological laboratories refered to as healthspan), showed that supplementation with nicotinamide delayed the onset of frailty, prolonged healthspan and lowered oxidative stress. This is another example of dissociation between oxidative stress and longevity. Supplemented animals that had lower oxidative stress, displayed signs of improved healthspan, delayed frailty, but did not show an increase in lifespan. Therefore, animal experiments, from both the molecular field as well as the nutritional field, show that there is a clear association between oxidative stress and delayed frailty, but that not an association between oxidative stress and chronological ageing. The experiments we have just reported provide experimental evidence in support of the free radical theory of frailty, but of course, human data were needed and this will be discussed in the next paragraph. The experiments in animals that we have just reported, led us to think that the same might occur in humans. One of the best characterised frailty-oriented
ACCEPTED MANUSCRIPT cohorts in Europe is the Toledo Frailty Study. This cohort, which has been followed up for more than fifteen years, is a very good source of information when trying to study ageing and especially frailty.
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We measured, for obvious ethical reasons only in blood plasma, parameters of oxidative stress in persons of ages ranging from 65 to 90. We determined lipid peroxidation as measured by malondialdehyde formation which was measured by HPLC. We also determined protein oxidation, determined by the presence of carbonylated proteins. In both cases, the former as an indication of lipid peroxidation and the latter as an indication of protein oxidation, we found no relationship between age and the increase in either of these two parameters. However, when we grouped individuals in three groups, one termed as controls or vigorous controls, the second termed as pre-frail individuals, and finally the third that we termed as frail individuals, we did indeed find that frail individuals had higher lipid peroxidation and protein oxidation than age-matched controls. Frailty was related to oxidative stress, but age was not [27]. This was the critical experiment that led us to formulate the free radical theory of frailty. It is important to emphasize that the most effective way to delay age associated diseases is to delay the loss of function that comes with frailty, as graphically shown in figure 2 lower panel
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5. Exercise does not prolong lifespan, but prevents frailty in mice: lack of activity is a cause of oxidative stress and frailty.
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In a long series of experiments that were performed in our laboratory we determined the effect of physical exercise on lifespan and on frailty in animals that were caged individually in a clean environment. The starting number of animals was 170. They were caged in such a way that they could run freely on a wheel that was placed in their cage. Longevity curves were determined and we observed that physical exercise does not increase lifespan, neither maximal nor average, in animals that are kept in a clean environment, without any type of stresses such as thermal or metabolic stress. However, when we determined the frailty status of the animals, we found that the exercise groups were less frail than controls [28]. This again was a further confirmation of the validity of the free radical theory of frailty. It indeed led us to perform a clinical trial on the effect of exercise on frailty that we report in the next paragraph.
6. Frailty can be reversed. Treatment of frailty with physical exercise The effect of exercise on the onset of frailty has been studied by various authors in the last three years. The majority of the studies have concentrated on persons who were institutionalised or on persons who were advised to perform exercise at their own homes. We decided to test whether controlled, multicomponent, personalised and social exercise would be effective in the
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prevention or even treatment of frailty. In our clinical trial, we had two populations of people of the same age who were subjected to exercise intervention. The exercise was multicomponent, including strength, aerobic and equilibrium phases. The results were very encouraging. The health of people who had exercised improved significantly and this ameliorated their health status by 56%, i.e. 56% of the patients were less frail than when they started the exercise. Moreover, other parameters, usually not reported when studying frailty, were improved. For instance, the number of visits to primary care fell by 45% in the exercise intervention group [29]. Other studies, such as the ACTIVNES, have concentrated on the synergistic effects of improving nutrition and increasing exercise [30]. Moreover, there was a full EU granted study led by Dr Rodriguez Manas that studied exercise performed individually at the home of the patient [31]. This was the Vivifrail Study. The major difference with the study we reported is that we increased the efficiency of exercise by promoting that patients performed it in groups. This not only ameliorates the physical status of the patients but also improves on the social capabilities. In any case, in all the clinical trials reported, physical exercise has shown to be a critical treatment for frailty as we proposed earlier, as we reported previously in this same Journal [32].
7.- Conclusion
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8. References
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The conclusion of these studies is that free radicals and oxidative stress are more related to frailty than to chronological age itself. The main conclusion comes from the fact that on many occasions ageing leads to frailty and the effects on ageing may be confused with those of frailty. Many of the studies reporting that ageing is independent of oxidative stress are indeed correct because they deal with healthy ageing frequently termed as healthspan. This free radical theory of frailty states that oxidative damage correlates with frailty and not with chronological ageing.
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from septuagenarians and reveals a role of Bcl-xL in successful aging, Aging (Albany NY) (2016). [22] J. Vina, C. Borras, M.C. Gomez-Cabrera, A free radical theory of frailty, Free Radic Biol Med 124 (2018) 358-363. [23] S.S. Deepa, S. Bhaskaran, S. Espinoza, S.V. Brooks, A. McArdle, M.J. Jackson, H. Van Remmen, A. Richardson, A new mouse model of frailty: the Cu/Zn superoxide dismutase knockout mouse, Geroscience 39(2) (2017) 187198. [24] S. Nobrega-Pereira, P.J. Fernandez-Marcos, T. Brioche, M.C. GomezCabrera, A. Salvador-Pascual, J.M. Flores, J. Vina, M. Serrano, G6PD protects from oxidative damage and improves healthspan in mice, Nat Commun 7 (2016) 10894. [25] M.C. Gomez-Cabrera, R. Garcia-Valles, L. Rodriguez-Manas, F.J. GarciaGarcia, G. Olaso-Gonzalez, A. Salvador-Pascual, F.J. Tarazona-Santabalbina, J. Vina, A New Frailty Score for Experimental Animals Based on the Clinical Phenotype: Inactivity as a Model of Frailty, J Gerontol A Biol Sci Med Sci 72(7) (2017) 885-891. [26] S.J. Mitchell, M. Bernier, M.A. Aon, S. Cortassa, E.Y. Kim, E.F. Fang, H.H. Palacios, A. Ali, I. Navas-Enamorado, A. Di Francesco, T.A. Kaiser, T.B. Waltz, N. Zhang, J.L. Ellis, P.J. Elliott, D.W. Frederick, V.A. Bohr, M.S. Schmidt, C. Brenner, D.A. Sinclair, A.A. Sauve, J.A. Baur, R. de Cabo, Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice, Cell Metab 27(3) (2018) 667-676 e4. [27] M. Ingles, J. Gambini, J.A. Carnicero, F.J. Garcia-Garcia, L. RodriguezManas, G. Olaso-Gonzalez, M. Dromant, C. Borras, J. Vina, Oxidative stress is related to frailty, not to age or sex, in a geriatric population: lipid and protein oxidation as biomarkers of frailty, J Am Geriatr Soc 62(7) (2014) 1324-8. [28] F. Derbre, A. Gratas-Delamarche, M.C. Gomez-Cabrera, J. Vina, Inactivityinduced oxidative stress: a central role in age-related sarcopenia?, Eur J Sport Sci 14 Suppl 1 (2014) S98-108. [29] G.-C.M. Tarazona-Santabalbina FJ1, Pérez-Ros P3, Martínez-Arnau FM4, Cabo H5, Tsaparas K5, Salvador-Pascual A5, Rodriguez-Mañas L6, Viña J5., A Multicomponent Exercise Intervention that Reverses Frailty and Improves Cognition, Emotion, and Social Networking in the Community-Dwelling Frail Elderly: A Randomized Clinical Trial., J Am Med Dir Assoc. 17(5) (2016) 426433. [30] P. Abizanda, M.D. Lopez, V.P. Garcia, D. Estrella Jde, A. da Silva Gonzalez, N.B. Vilardell, K.A. Torres, Effects of an Oral Nutritional Supplementation Plus Physical Exercise Intervention on the Physical Function, Nutritional Status, and Quality of Life in Frail Institutionalized Older Adults: The ACTIVNES Study, J Am Med Dir Assoc 16(5) (2015) 439 e9-439 e16. [31] M. Izquierdo, L. Rodriguez-Manas, A.J. Sinclair, Editorial: What Is New in Exercise Regimes for Frail Older People - How Does the Erasmus Vivifrail Project Take Us Forward?, J Nutr Health Aging 20(7) (2016) 736-7. [32] J. Vina, A. Salvador-Pascual, F.J. Tarazona-Santabalbina, L. RodriguezManas, M.C. Gomez-Cabrera, Exercise training as a drug to treat age associated frailty, Free Radic Biol Med 98 (2016) 159-164.
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Figure 1.- The problem of frailty and disability
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Panel a shows the percent of individuals over 65 years of age that are disabled in the EU and estimation that, unless urgent action is taken, in 2050 half of the European population over 65 will be dependent (Courtesy of Dr JP Bolaños, Salamanca). Panel b shows that the economic cost of taking care of an elderly person with severe disability is more than 15 times that of a robust one. (Drawn by Dr MC Gomez- Cabrera, Valencia)
Figure 2.- Oxidative damage and the transition from frailty to disability
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The double edge of oxidation in the context of aging is shown: The top part describes physiological oxidative stress leading to healthy aging and robustness in old age. The lower part shows the situation when free radical damage occurs: frailty and later on disability lead to unsuccessful aging. This figure is reproduced (with permission) from reference 22
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Chronological aging is not always associated with oxidative damage Frailty is a geriatric syndrome by which an older person displays increased vulnerability to minor stresses Frailty increases the risk of disability and eventually death The free radical theory of frailty proposes that oxidative damage is not associated with aging but with frailty This theory provides a rationale to prevent or delay frailty by interventions aiming to protect against oxidative damage
S0891-5849(18)32651-0
DOI:
https://doi.org/10.1016/j.freeradbiomed.2019.01.045
Reference:
FRB 14143
To appear in:
Free Radical Biology and Medicine
Received Date: 30 December 2018 Revised Date:
30 January 2019
Accepted Date: 31 January 2019
Please cite this article as: J. Viña, The free radical theory of frailty: Mechanisms and opportunities for interventions to promote successful aging, Free Radical Biology and Medicine (2019), doi: https:// doi.org/10.1016/j.freeradbiomed.2019.01.045. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Adaptation to exercise, nutrition or micronutrient supplements
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Oxidative damage vs oxidative stress in the pathophysiology of frailty
Mitochondrial damage, pollution radiation, unsucesful aging
ACCEPTED MANUSCRIPT INVITED MINI REVIEW FREE RADICAL BIOLOGY AND MEDICINE The free radical theory of frailty: mechanisms interventions to promote successful aging.
and
opportunities
for
Jose Viña, MD, PhD
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Affiliation: Freshage Research Group-Department of Physiology, Faculty of Medicine, University of Valencia, CIBERFES and INCLIVA, Avenida Blasco Ibañez nº 15, 46010, Valencia, Spain. Address correspondence to: Dr. Jose Vina
Av. Blasco Ibañez, 15, 46010, Valencia, Spain.
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Department of Physiology. Faculty of Medicine. University of Valencia.
Email: [email protected]
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Phone: (34) 96 386 46 50; Fax: (34) 96 386 46 42
Conflict of interest: The author declares that no conflict of interest exists.
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Acknowledgements: Work from the author’s laboratory was supported by the following grants: Instituto de Salud Carlos III and co-funded by FEDER [grant number PIE15/00013], SAF2016-75508-R from the Spanish Ministry of Education and Science (MEC), CB16/10/00435 (CIBERFES), EU Funded FRAILOMIC-HEALTH.2012.2.1.1-2 and ADVANTAGE-724099 Join Action (HPJA) 3rd EU Health Programme.
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The author thanks Mrs. Marilyn Noyes for her kind help in reviewing the manuscript and Drs Gomez-Cabrera and Borras for their help with this paper.
ACCEPTED MANUSCRIPT ABSTRACT
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The free radical theory of ageing has provided a framework of research into ageing based on Harman’s idea that ageing was caused by damage produced by free radicals. However, several experiments have cast doubts on the general validity of the theory. The postulation of the free radical theory of frailty came from two basic facts: first that radicals not only act as damaging molecules, but also as signals to control cell function and second that on many occasions oxidative damage does not correlate with chronological but rather with unsuccessful ageing. Frailty is a geriatric concept by which an older person shows a lack of the feeling of wellbeing, unintentional weight loss, a relatively low grip strength, lowering the speed of walking, and difficulties to stand. If left untreated, frailty progresses to disability. Many interventions that prevent oxidative damage to cells do not affect longevity but have a clear effect on the prevention of frailty and its transition to disability. Clinical trials have shown that exercise programmes do not promote longevity but delay the onset of frailty. Experiments and mechanisms to support this idea are described.
ACCEPTED MANUSCRIPT 1.-The free radical theory of aging: relevance and the debate on its validity. Pros and cons of the free radical theory of aging.
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Postulating theories to understand ageing has been a major undertaking of biogerontologists for over a century. Of the more than 300 theories of ageing that we found in a review of the literature in 2007 [1], the free radical theory was one of the most interesting because it provided not only a mechanism to understand damage associated with ageing (this, according to the theory, was damage caused by oxygen radicals), but it also provided room for intervention as antioxidants could be administered to delay or prevent the damage caused by oxidants.
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Interest in oxidative free radicals was greatly boosted by the finding of Rebecca Gershman that radiation-induced injury could be attributed to the effects of oxygen radicals. This was published back in 1955 [2]. One year later, in a classic paper, Denham Harman proposed his free radical theory of ageing that stated that “ageing and degenerative diseases associated with it are attributed basically to the deleterious side attacks of free radicals on cell constituents and on the connective tissues” [3]. This is literally Harman’s formulation of the free radical theory of ageing where he, with great hindsight, proposed that damage associated with ageing or interestingly associated with degenerative diseases that come with age, could be due to the effects of free radicals on cell constituents. The obvious corollary to this theory was that the administration of antioxidants would be good for your health as it would prevent damage associated with these radicals that leads to ageing and to degenerative diseases. A great boost to the general idea that disease could be associated with oxidation and that antioxidants would be beneficial came from the ideas of a genius of the stature of Linus Pauling. In his widely read book “Vitamin C, the Common Cold and the Flu” [4]. Linus Pauling proposed that administration of high doses (on some occasions enormous doses) of vitamin C could lead to an efficacious prevention of the common cold and of the flu, a disease that causes thousands of deaths every year, especially among the older population.
This was how the scene was around the mid-70s and twenty-five years were to pass before critical experiments could be performed that disproved the general validity of Harman’s free radical theory of ageing.
But around the turn of the century, two critical ideas came to the forefront of radical research and changed our interpretation of how free radicals interact with living matter. The first was that free radicals could act as signals [5, 6] and not just as damaging molecules. Radicals were in the cell to contribute to the wonderfully complex web of signals that allow different metabolic pathways to act in a smooth synergistic way. The second idea was that it is better to promote endogenous antioxidant enzymes, such as superoxide dismutases,
ACCEPTED MANUSCRIPT catalase, glutathione peroxidases, etc. rather than giving exogenous antioxidant molecules, usually low molecular weight, such as vitamin C or E [7]. Thus, the idea of a normal level of oxygen species having a function in regulating cell metabolism, and in general cell life, became entrenched in the minds of researchers and led to critical experiments to try and disprove [8] the free radical theory of ageing [3].
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Thus a number of experiments became available showing that the free radical theory of ageing was still valid, but a number of others clearly showed that this was not the case. I shall now refer to some of them showing how difficult the situation was for researchers in the field because of the discrepancies regarding the validity of the free radical theory of ageing. Moosmann and Behl [9] in 2008 published results that literally “provided distinct support for the free radical theory of ageing”. But, on the other hand, the laboratory of Arlan Richardson in a review published in 2009 described that “data calls into serious question the hypothesis that alterations in oxidative damage play a role in the longevity of mice” [10]. The actual title of the paper was “Is the oxidative stress theory of ageing dead?”. Then a paper in Experimental Gerontology by an international group that included researchers of the level of Tomas Prolla, Gustavo Barja, or Christiaan Leeuwenburg provided results that gave full support to the mitochondrial free radical theory of ageing [11]. Many other papers were published with some in favour, but some were clearly showing that the free radical theory of ageing was difficult to reconcile with the available evidence, at least as postulated by Harman. Importantly, the laboratory of Hekimi reported that superoxide signals triggers increase longevity in C. elegans thus concluding that the findings were not consistent with the free radical theory of ageing [12]. But, on the other hand, in a review paper published in 2011 in Nature, Kelly placed reactive oxygen species (as he named them) precisely in the middle of the causes of damage associated with ageing [13]. Many other reports on experiments against the free radical theory of ageing could be mentioned here, but I shall only mention work from our own laboratory in which the main corollary, i.e. that antioxidants are advantageous is disproved. By 2008, we observed that feeding rats with high doses of vitamin C did prevent the adaptations of muscle to physical training [14]. The idea that radicals associated with exercise could trigger mitochondriogenesis had initially been put forward by Davies, Quintanilha, Brooks and Packer in their classic 1982 paper on physical exercise [15]. What we did was to show that training in both rats and humans was greatly hindered by administration of high doses of vitamin C and the explanation was that not only mitochondrial biogenesis was impaired, but that the increased expression of antioxidant enzymes could also be impaired by administration of antioxidants. One year later, i.e. in 2009, Michael Ristow and colleagues showed that antioxidant administration not only hinders the improvements in physical performance associated with exercise, but it also diminishes the improvements in health status associated with exercise [16].
ACCEPTED MANUSCRIPT To sum up we, and others, reported facts that go firmly against the idea that oxidation associated with exercise is always bad and that one should not take antioxidants without critical hesitation.
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The experiments and thoughts we have just reported here indicate that the general idea of the free radical theory of ageing useful as it was and is, had to be revised to cope with the new evidence showing that oxygen radicals were not always bad for your health. 2.- Definition of frailty, disability and intrinsic capacity
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One of the major new concepts in geriatrics in the last two decades is the identification of the frailty phenotype. This was put forward by researchers at Johns Hopkins School of Medicine in Baltimore led by Linda Fried and Jeremy Walston [17]. The phenotype of the frail old individual has been described in many publications, symposia have been devoted to it, and even EU projects have been granted to reach a definition of frailty [18].. Frailty is a geriatric syndrome by which an older person displays increased vulnerability to minor stresses. A frail person feels a lack of well-being, unintentional weight loss, a relatively low grip strength, slow walking speed, and difficulties to stand. If left untreated, frailty progresses to disability
If a young person shows some of the traits of frailty that I have just mentioned, then it is not a case of frailty but rather a specific disease
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The physiology behind this lack of energy is probably the fact that frail persons do not have the capacity to react against stresses that the vigorous ones have. The most important corollary of the frailty status is that eventually it leads to disability. Figure 1, top panel shows the predictions of the European Union at its meeting in Lisbon in 2000 that by the year 2020 approximately 30% of the European population over 65 will be frail, but that the situation worsens rapidly and that by 2050, half of the European population over 65 will be frail or even disabled. This indicates that the personal, medical, social and economic weight of disability is going to become, or has already become, a major problem and an opportunity for society today. The estimated cost of disability is shown in the lower panel of Figure 1 lower panel. A robust old person requires only 900 € per year whereas a dependent one requires more than 14000 €, in increase of more than 16 fold. The importance of frailty in the clinical scenario has already been described [19]. The idea of frailty as leading to disability, has prompted much reflection in the scientific community and recently the World Health Organization (WHO) has put forward the idea of the intrinsic capacity. In essence, intrinsic capacity seems to be the opposite of frailty, i.e., if a person has high intrinsic capacity then it is unlikely that he/she will become frail. In fact, the WHO defines intrinsic capacity as “the composite of all physical and mental capacities that an individual can draw upon at any point of their life”. Healthy ageing was defined as “the process of developing and maintaining functional ability that enables wellbeing in older age”. The claim is that healthy ageing depends finally on the
ACCEPTED MANUSCRIPT intrinsic capacity of an individual and the interaction of this individual with his/her environment.
A most important point is that the individual variations of intrinsic capacity in general terms increase with age. Thus, there will be more differences between two individuals in older age than in younger age in terms of intrinsic capacity.
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This has not been defined in clear clinical terms as has frailty, but it helps to shift attention from public health measures of health promotion, such as vaccination or systematic search for age-associated. Needless to say, the newer concept of intrinsic capacity immediately brings forward the idea that each individual should try and promote their own intrinsic capacity, certainly under the close scrutiny of healthcare professionals [20]. Programmes of physical exercise, that must be personalised (in the framework of stratified, i.e. not just adjusted for one person, but for groups of persons with similar intrinsic capacity) must also be multicomponent taking into account at least three approaches (aerobic, strength and equilibrium types of exercise) and must be social because experience tells us that the adherence of exercise when practised in a social context is much higher than when practised individually. As I shall describe later on in this paper, free radicals are much more involved in the process of developing frailty than in ageing itself
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3.- Formulation of the free radical theory of frailty
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The basic facts that we considered to propose as a hypothesis that oxidative stress is related to frailty and not to ageing are the following: In the first place, ageing is not always associated with oxidative stress (as described above). In second term ageing is often associated with frailty, and is also often associated with oxidative damage. Finally, we observed both in animals and in humans, that ageing itself is not associated with oxidative damage but that only unsuccessful ageing is associated with oxidation. Further confirmation of this hypothesis came from work in centenarians who enjoy a long, productive and in many cases disease-free old age and whose oxidative stress is in many cases lower than that we observe in octogenarians [21]. The hypothesis, therefore, was that ageing could be dissociated from oxidative damage and that only unsuccessful ageing i.e. frailty, could be associated with oxidative damage. Figure 2 top panel graphically describes the idea that contolled oxidative stress leads to successful aging and that only uncontrolled stress leads to damage. Thus, we proposed in this Journal our free radical theory of frailty [22] . This theory states that frailty is associated with oxidative damage to tissues and to macromolecules. Experiments must be devised to try and disprove the theory [8]. Thus, we and others set out to try and disprove this free radical theory of frailty.
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The free radical theory of frailty has been tested in both experimental animals and humans. The general approach to the experimental animal has been twosided: from one side the development of animals that were either suffering high oxidative stress or suffering low oxidative stress could result respectively in increased frailty or decreased frailty, but without changes in longevity. Another approach has been to supplement animals with, for instance, nicotinamide riboside resulting in alterations in oxidative stress that did not lead to changes in longevity, but that affect what researchers termed as “healthspan”.
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We would like to mention here that in many biological papers, researchers refer to healthspan whereas in the clinical scenario, clinicians tend to refer more to frailty and eventual disability rather to the loss of healthspan. After pondering the observations of both experimental researchers and clinicians, I tend to conclude that both terms can be used for our purposes at least, interchangeably. In any case, I shall go on using the term frailty for the purposes of this review paper. The tests to the theory have also provided mechanisms that we can use to approach the problem at hand. This is the emphasis of this paper: that understanding mechanisms can lead to us to better refine the free radical theory of frailty and to better understand the concept of healthspan which can also be correlated with that of intrinsic capacity.
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As stated above, two different molecular approaches have been used to tackle the problem of the relationship between ageing, frailty and oxidative stress. In the first instance, an excellent group of researchers from both the USA (Arlan Richardson and his group) as well as from the UK (Malcolm Jackson and his group) generated a superoxide-dismutase-deficient mouse (SOD-/-) [23]. As expected, this animal suffered from high oxidative stress and high oxidative damage because a critical enzyme to detoxify superoxide was absent. The animal, however, did not live less than the controls, but most interestingly, the quality of life, i.e. the healthspan was considerably decreased and the onset of frailty accelerated. This was a most important test of the free radical theory of frailty: increasing oxidative stress by molecular means does not lead to decreased longevity but rather to increased frailty. But there is another approach that could be used that is almost the “other side of the coin” of the experiments we have just described. And this was carried out by our laboratory in cooperation with that of Dr Manuel Serrano from Barcelona. Our aim was to generate a mouse that overexpresses glucose 6 phosphate dehydrogenase (G6PD) [24]. G6PD is a critical enzyme in the generation of reducing equivalents in the form of NADP. In my opinion, it is most important because it provides (from glucose) a continuous flow of reducing equivalents to counteract the continuous flow of oxidising equivalents that come essentially from oxygen. A complete network of antioxidant mechanisms exists between
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the NADPH and superoxide, but the initial event in terms of pro-oxidation comes from oxygen whereas the initial event in anti-oxidation comes from glucose through G6PD. We thus generated the G6PD overexpressing mouse and observed that it does confer a significant protection against oxidative stress, a remarkable increase in resistance against oxidation by agents such as diamide, but no significant changes in longevity. Only a relatively minor change in longevity only in females could be observed. But we found that this animal is seriously protected against metabolic stresses.
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Unpublished experiments from our laboratory show that the G6PD overexpressing mouse displays a delay in the onset of frailty. We have achieved this by using a new frailty index that we have developed that is called “Valencia index for frailty in experimental animals” [25]. This is an index that we developed based on the criteria that have been used in the clinical setting, especially derived from the work of Linda Fried and co-workers [17]. The animals that were expressing G6PD display a clear delay in the onset of frailty as determined by our Valencia index of frailty.
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So animals that suffer high oxidative stress (SOD-/-) or low oxidative stress (G6PD) live the same as their controls: longevity is dissociated from oxidative stress, but in both cases the animals that have higher oxidative stress show earlier signs of frailty and those that have lower oxidative stress display an increased healthspan and delay in frailty.
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The validity of the free radical theory of frailty has also come from experiments in which the animals were treated with oral supplements rather than with molecular alterations of the genome expression. Experiments in which nutritional supplementation increases healthspan, but not lifespan, have been performed in several laboratories. I shall discuss here a critical paper from the de Cabo laboratory [26]. In this paper, the authors supplemented mice with nicotinamide riboside and they observed that the longevity of both treated and untreated was unchanged. However, measures of parameters that are usually considered part of any frailty index (as is usual in biological laboratories refered to as healthspan), showed that supplementation with nicotinamide delayed the onset of frailty, prolonged healthspan and lowered oxidative stress. This is another example of dissociation between oxidative stress and longevity. Supplemented animals that had lower oxidative stress, displayed signs of improved healthspan, delayed frailty, but did not show an increase in lifespan. Therefore, animal experiments, from both the molecular field as well as the nutritional field, show that there is a clear association between oxidative stress and delayed frailty, but that not an association between oxidative stress and chronological ageing. The experiments we have just reported provide experimental evidence in support of the free radical theory of frailty, but of course, human data were needed and this will be discussed in the next paragraph. The experiments in animals that we have just reported, led us to think that the same might occur in humans. One of the best characterised frailty-oriented
ACCEPTED MANUSCRIPT cohorts in Europe is the Toledo Frailty Study. This cohort, which has been followed up for more than fifteen years, is a very good source of information when trying to study ageing and especially frailty.
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We measured, for obvious ethical reasons only in blood plasma, parameters of oxidative stress in persons of ages ranging from 65 to 90. We determined lipid peroxidation as measured by malondialdehyde formation which was measured by HPLC. We also determined protein oxidation, determined by the presence of carbonylated proteins. In both cases, the former as an indication of lipid peroxidation and the latter as an indication of protein oxidation, we found no relationship between age and the increase in either of these two parameters. However, when we grouped individuals in three groups, one termed as controls or vigorous controls, the second termed as pre-frail individuals, and finally the third that we termed as frail individuals, we did indeed find that frail individuals had higher lipid peroxidation and protein oxidation than age-matched controls. Frailty was related to oxidative stress, but age was not [27]. This was the critical experiment that led us to formulate the free radical theory of frailty. It is important to emphasize that the most effective way to delay age associated diseases is to delay the loss of function that comes with frailty, as graphically shown in figure 2 lower panel
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5. Exercise does not prolong lifespan, but prevents frailty in mice: lack of activity is a cause of oxidative stress and frailty.
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In a long series of experiments that were performed in our laboratory we determined the effect of physical exercise on lifespan and on frailty in animals that were caged individually in a clean environment. The starting number of animals was 170. They were caged in such a way that they could run freely on a wheel that was placed in their cage. Longevity curves were determined and we observed that physical exercise does not increase lifespan, neither maximal nor average, in animals that are kept in a clean environment, without any type of stresses such as thermal or metabolic stress. However, when we determined the frailty status of the animals, we found that the exercise groups were less frail than controls [28]. This again was a further confirmation of the validity of the free radical theory of frailty. It indeed led us to perform a clinical trial on the effect of exercise on frailty that we report in the next paragraph.
6. Frailty can be reversed. Treatment of frailty with physical exercise The effect of exercise on the onset of frailty has been studied by various authors in the last three years. The majority of the studies have concentrated on persons who were institutionalised or on persons who were advised to perform exercise at their own homes. We decided to test whether controlled, multicomponent, personalised and social exercise would be effective in the
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prevention or even treatment of frailty. In our clinical trial, we had two populations of people of the same age who were subjected to exercise intervention. The exercise was multicomponent, including strength, aerobic and equilibrium phases. The results were very encouraging. The health of people who had exercised improved significantly and this ameliorated their health status by 56%, i.e. 56% of the patients were less frail than when they started the exercise. Moreover, other parameters, usually not reported when studying frailty, were improved. For instance, the number of visits to primary care fell by 45% in the exercise intervention group [29]. Other studies, such as the ACTIVNES, have concentrated on the synergistic effects of improving nutrition and increasing exercise [30]. Moreover, there was a full EU granted study led by Dr Rodriguez Manas that studied exercise performed individually at the home of the patient [31]. This was the Vivifrail Study. The major difference with the study we reported is that we increased the efficiency of exercise by promoting that patients performed it in groups. This not only ameliorates the physical status of the patients but also improves on the social capabilities. In any case, in all the clinical trials reported, physical exercise has shown to be a critical treatment for frailty as we proposed earlier, as we reported previously in this same Journal [32].
7.- Conclusion
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8. References
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The conclusion of these studies is that free radicals and oxidative stress are more related to frailty than to chronological age itself. The main conclusion comes from the fact that on many occasions ageing leads to frailty and the effects on ageing may be confused with those of frailty. Many of the studies reporting that ageing is independent of oxidative stress are indeed correct because they deal with healthy ageing frequently termed as healthspan. This free radical theory of frailty states that oxidative damage correlates with frailty and not with chronological ageing.
[1] J. Vina, C. Borras, J. Miquel, Theories of ageing, IUBMB Life 59(4-5) (2007) 249-54. [2] R. Gershman, Gilbert, D.L., Nye, S.W., Dwyer, P., Fenn, W.O., Oxygen poisoning and X irradiation: a mechanism in common., Science 119 (1954) 623626. [3] D. Harman, Aging: a theory based on free radical and radiation chemistry., J. Gerontol. 2 (1956) 298-300. [4] L. Pauling, Vitamin C, the common cold and the flu., Ed. Freeman S. Francisco (1973). [5] T. Finkel, Reactive oxygen species and signal transduction, IUBMB Life 52(1-2) (2001) 3-6. [6] T. Finkel, Signal transduction by reactive oxygen species, J Cell Biol 194(1) (2011) 7-15.
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[7] J. Vina, M.C. Gomez-Cabrera, C. Borras, Fostering antioxidant defences: up-regulation of antioxidant genes or antioxidant supplementation?, Br J Nutr 98 Suppl 1 (2007) S36-40. [8] K.R. Popper, The Logic of Scientific Discovery, Basic Books, Inc., New York, 1959. [9] B. Moosmann, C. Behl, Mitochondrially encoded cysteine predicts animal lifespan, Aging Cell 7(1) (2008) 32-46. [10] V.I. Perez, A. Bokov, H. Van Remmen, J. Mele, Q. Ran, Y. Ikeno, A. Richardson, Is the oxidative stress theory of aging dead?, Biochim Biophys Acta 1790(10) (2009) 1005-14. [11] A. Sanz, A. Hiona, G.C. Kujoth, A.Y. Seo, T. Hofer, E. Kouwenhoven, R. Kalani, T.A. Prolla, G. Barja, C. Leeuwenburgh, Evaluation of sex differences on mitochondrial bioenergetics and apoptosis in mice, Exp Gerontol 42(3) (2007) 173-82. [12] W. Yang, S. Hekimi, A mitochondrial superoxide signal triggers increased longevity in Caenorhabditis elegans, PLoS Biol 8(12) (2010) e1000556. [13] D.P. Kelly, Cell biology: Ageing theories unified, Nature 470(7334) (2011) 342-3. [14] M.C. Gomez-Cabrera, E. Domenech, M. Romagnoli, A. Arduini, C. Borras, F.V. Pallardo, J. Sastre, J. Vina, Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance, Am J Clin Nutr 87(1) (2008) 142-9. [15] K.J.A. Davies, A.T. Quintanilha, G.A. Brooks, L. Packer, Free radicals and tissue damage produced by exercise., Biochem. Biophys. Res. Commun. 107 (1982) 1198-1205. [16] M. Ristow, K. Zarse, A. Oberbach, N. Kloting, M. Birringer, M. Kiehntopf, M. Stumvoll, C.R. Kahn, M. Bluher, Antioxidants prevent health-promoting effects of physical exercise in humans, Proc Natl Acad Sci U S A 106(21) (2009) 866570. [17] L.P. Fried, C.M. Tangen, J. Walston, A.B. Newman, C. Hirsch, J. Gottdiener, T. Seeman, R. Tracy, W.J. Kop, G. Burke, M.A. McBurnie, G. Cardiovascular Health Study Collaborative Research, Frailty in older adults: evidence for a phenotype, J Gerontol A Biol Sci Med Sci 56(3) (2001) M146-56. [18] L. Rodriguez-Manas, C. Feart, G. Mann, J. Vina, S. Chatterji, W. ChodzkoZajko, M. Gonzalez-Colaco Harmand, H. Bergman, L. Carcaillon, C. Nicholson, A. Scuteri, A. Sinclair, M. Pelaez, T. Van der Cammen, F. Beland, J. Bickenbach, P. Delamarche, L. Ferrucci, L.P. Fried, L.M. Gutierrez-Robledo, K. Rockwood, F. Rodriguez Artalejo, G. Serviddio, E. Vega, Searching for an Operational Definition of Frailty: A Delphi Method Based Consensus Statement. The Frailty Operative Definition-Consensus Conference Project, J Gerontol A Biol Sci Med Sci 68(1) (2012) 62-67. [19] L. Rodriguez-Manas, L.P. Fried, Frailty in the clinical scenario, Lancet 385(9968) (2015) e7-9. [20] M.F. de Carvalho IA, Cesari M, Sumi Y, Thiyagarajan JA, Beard JR. , Operationalizing the concept of intrinsic capacity in clinical settings., WHO Clinical Consortium on Healthy Ageing (CCHA) Meeting 2017 (2017). [21] C. Borras, K.M. Abdelaziz, J. Gambini, E. Serna, M. Ingles, M. de la Fuente, I. Garcia, A. Matheu, P. Sanchis, A. Belenguer, A. Errigo, J.A. Avellana, A. Barettino, C. Lloret-Fernandez, N. Flames, G. Pes, L. Rodriguez-Manas, J. Vina, Human exceptional longevity: transcriptome from centenarians is distinct
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from septuagenarians and reveals a role of Bcl-xL in successful aging, Aging (Albany NY) (2016). [22] J. Vina, C. Borras, M.C. Gomez-Cabrera, A free radical theory of frailty, Free Radic Biol Med 124 (2018) 358-363. [23] S.S. Deepa, S. Bhaskaran, S. Espinoza, S.V. Brooks, A. McArdle, M.J. Jackson, H. Van Remmen, A. Richardson, A new mouse model of frailty: the Cu/Zn superoxide dismutase knockout mouse, Geroscience 39(2) (2017) 187198. [24] S. Nobrega-Pereira, P.J. Fernandez-Marcos, T. Brioche, M.C. GomezCabrera, A. Salvador-Pascual, J.M. Flores, J. Vina, M. Serrano, G6PD protects from oxidative damage and improves healthspan in mice, Nat Commun 7 (2016) 10894. [25] M.C. Gomez-Cabrera, R. Garcia-Valles, L. Rodriguez-Manas, F.J. GarciaGarcia, G. Olaso-Gonzalez, A. Salvador-Pascual, F.J. Tarazona-Santabalbina, J. Vina, A New Frailty Score for Experimental Animals Based on the Clinical Phenotype: Inactivity as a Model of Frailty, J Gerontol A Biol Sci Med Sci 72(7) (2017) 885-891. [26] S.J. Mitchell, M. Bernier, M.A. Aon, S. Cortassa, E.Y. Kim, E.F. Fang, H.H. Palacios, A. Ali, I. Navas-Enamorado, A. Di Francesco, T.A. Kaiser, T.B. Waltz, N. Zhang, J.L. Ellis, P.J. Elliott, D.W. Frederick, V.A. Bohr, M.S. Schmidt, C. Brenner, D.A. Sinclair, A.A. Sauve, J.A. Baur, R. de Cabo, Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice, Cell Metab 27(3) (2018) 667-676 e4. [27] M. Ingles, J. Gambini, J.A. Carnicero, F.J. Garcia-Garcia, L. RodriguezManas, G. Olaso-Gonzalez, M. Dromant, C. Borras, J. Vina, Oxidative stress is related to frailty, not to age or sex, in a geriatric population: lipid and protein oxidation as biomarkers of frailty, J Am Geriatr Soc 62(7) (2014) 1324-8. [28] F. Derbre, A. Gratas-Delamarche, M.C. Gomez-Cabrera, J. Vina, Inactivityinduced oxidative stress: a central role in age-related sarcopenia?, Eur J Sport Sci 14 Suppl 1 (2014) S98-108. [29] G.-C.M. Tarazona-Santabalbina FJ1, Pérez-Ros P3, Martínez-Arnau FM4, Cabo H5, Tsaparas K5, Salvador-Pascual A5, Rodriguez-Mañas L6, Viña J5., A Multicomponent Exercise Intervention that Reverses Frailty and Improves Cognition, Emotion, and Social Networking in the Community-Dwelling Frail Elderly: A Randomized Clinical Trial., J Am Med Dir Assoc. 17(5) (2016) 426433. [30] P. Abizanda, M.D. Lopez, V.P. Garcia, D. Estrella Jde, A. da Silva Gonzalez, N.B. Vilardell, K.A. Torres, Effects of an Oral Nutritional Supplementation Plus Physical Exercise Intervention on the Physical Function, Nutritional Status, and Quality of Life in Frail Institutionalized Older Adults: The ACTIVNES Study, J Am Med Dir Assoc 16(5) (2015) 439 e9-439 e16. [31] M. Izquierdo, L. Rodriguez-Manas, A.J. Sinclair, Editorial: What Is New in Exercise Regimes for Frail Older People - How Does the Erasmus Vivifrail Project Take Us Forward?, J Nutr Health Aging 20(7) (2016) 736-7. [32] J. Vina, A. Salvador-Pascual, F.J. Tarazona-Santabalbina, L. RodriguezManas, M.C. Gomez-Cabrera, Exercise training as a drug to treat age associated frailty, Free Radic Biol Med 98 (2016) 159-164.
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Figure 1.- The problem of frailty and disability
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Panel a shows the percent of individuals over 65 years of age that are disabled in the EU and estimation that, unless urgent action is taken, in 2050 half of the European population over 65 will be dependent (Courtesy of Dr JP Bolaños, Salamanca). Panel b shows that the economic cost of taking care of an elderly person with severe disability is more than 15 times that of a robust one. (Drawn by Dr MC Gomez- Cabrera, Valencia)
Figure 2.- Oxidative damage and the transition from frailty to disability
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The double edge of oxidation in the context of aging is shown: The top part describes physiological oxidative stress leading to healthy aging and robustness in old age. The lower part shows the situation when free radical damage occurs: frailty and later on disability lead to unsuccessful aging. This figure is reproduced (with permission) from reference 22
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Chronological aging is not always associated with oxidative damage Frailty is a geriatric syndrome by which an older person displays increased vulnerability to minor stresses Frailty increases the risk of disability and eventually death The free radical theory of frailty proposes that oxidative damage is not associated with aging but with frailty This theory provides a rationale to prevent or delay frailty by interventions aiming to protect against oxidative damage