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Prevention and intervention
Experimental Gerontology 48 (2013) 6–7
Contents lists available at SciVerse ScienceDirect
Experimental Gerontology journal homepage: www.elsevier.com/locate/expgero
Editorial
Prevention and intervention It is well known that age is a major risk factor for many degenerative diseases. There are several theories related to aging and its degenerative processes. The aging process is, however, mostly driven by the lifelong accumulation of stochastic forms of damage (e.g. oxidation or glycation of the macromolecules). This damage modifies the tissue and, depending on the tissue involved, might be construed as specific risk factors for diseases. This was mentioned by Ed Lakatta (2002) as: “age-associated changes in cardiac and vascular properties alter the substrate upon which cardiovascular disease is superimposed”. On the other hand, a long life expectancy is driven by enhanced repair systems of damage. In light of this view, diseases may be the late outcome of a lifelong damaging process in combination with reduced repair capacities. Therefore, prevention is the only possibility to avoid the early occurrence of degenerative diseases. Preventive medicine refers to actions taken to prevent diseases or injuries rather than curing them. Prevention aims to promote health and it contrasts in methods with curative or palliative medicine. Primary prevention strategies intend to avoid the development of disease at very early stages because often the roots of old age diseases are in childhood or in middle-age. Secondary prevention strategies attempt to treat an existing disease in its early stages before it results in significant morbidity or complications. Treatment of cardiovascular risk factors in diabetes to prevent morbidity is a typical example of secondary prevention. Treatments in tertiary prevention aim to reduce the negative impact of an established disease by restoring function and reducing disease-related complications. Treatment of stroke patient's atrial fibrillation with anticoagulant is a typical example of tertiary prevention. Primary prevention strategies – such as physical exercise – can be beneficial until very old age. However, prevention in old age can often be defined as secondary or tertiary prevention. In old age secondary prevention strategies aim to prevent geriatric syndromes such as cardiovascular diseases, cognitive decline, frailty or falls. Tertiary prevention aims to restore functioning, autonomy and quality-of-life among those already suffering from geriatric syndromes. Intervention studies are used in clinical medicine to test which preventive and treatment strategies are beneficial. Evidence-based medicine considers rigorously performed randomized, controlled clinical trials and their meta-analyses as the top level of evidence on effectiveness of treatment. There is growing body of evidence that various preventive strategies are highly effective in very old age: for example exercise in improving mobility limitations (Liu and Latham, 2009), antihypertensives in preventing cardiovascular morbidity (Musini et al., 2009), statins in primary (Roberts et al., 2007) and secondary prevention for vascular diseases (Afilalo et al, 2008), or various strategies in preventing falls (AGS, 2011). However, we have to be highly aware in which kind of patient or target group these treatments have been tested and to which patient group we ought to implement these treatments (Guyatt et al., 1994). 0531-5565/$ – see front matter © 2012 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.exger.2012.11.002
Still, there are large gaps in our knowledge, especially concerning the frailest and oldest-old: how to help them avoid further complications? How did their geriatric syndromes develop? Especially we know too little about dementia. The dilemma exists: are we too late in old age to prevention? Should we start earlier and how? Many age-related diseases take decades to develop, and we still know too little about the mechanisms behind them. Clinical studies can only test hypotheses that are created in basic science. We need more cooperation between basic scientists, especially biogerontologists, and clinical scientists. In addition, we need translational medical scientists. Translational medicine is research facilitating the translation of findings from basic science to practical applications that enhance human health and well-being. The Halle international meeting 2011 “Prevention and intervention: from molecular biology to clinical perspectives” aimed to gather together and enhance communication among gerontologists working on mechanisms of aging, translational scientists and geriatricians. The keynote speaker and Schober-prize winner, Kaisu Pitkälä from Finland, gave an overview of what kind of evidence exists on preventive strategies in old age populations and what kinds of gaps there are in our knowledge concerning this topic. This issue of Experimental Gerontology gives an overview of the topics presented and the issues discussed in that meeting. Therefore, there are articles on basic science and translational research as well as on clinical medicine. The articles in this issue aim to bridge gaps between, e.g. cardiovascular risk factors to cardiovascular aging process and diseases, and they shed light on mechanisms behind development of sarcopenia and possibilities to prevent it. Using experimental settings like cell cultures or animal models, mechanisms can be identified and investigated which can be further proven in humans. Conserved mechanisms between species can be used to develop biomarkers of aging, which, at the end, may be useful to test the effectiveness of preventive actions. In this regard, Büchner et al. investigated the effect of an unhealthy (fructose and LDL rich) diet and ultrafine carbon black particles (ufCB, as an example of air pollution) on cardiovascular cells. Interestingly, fructose and LDL enriched media induce age related cellular changes like cardiomyocyte hypertrophy, smooth muscle cell proliferation and senescence in endothelial cells. UfCB induces oxidative stress, inhibits telomerase activity and induces cellular senescence in endothelial cells. This indicates the direct impact of the environment on cellular aging. Whereas in mammalians, cellular senescence seems to be important for the lifespan of the organism, Graf et al. showed in contrast, that this is not true for all species. In the model of the short-lived killifish Nothobranchius furzeri, known markers for cellular senescence do not correlate with the age of the fish. Furthermore, the authors cannot detect replicative senescence in primary cell culture models. Another mechanism of aging is the accumulation of glycated proteins in the extracellular matrix of tissues.
Editorial
Indeed, Rolewska et al. showed in the aging mouse lung model, that the fibrillar collagen of the mouse lung tissue displayed a lower enzymatic solubility and increased the amount of the post-translational modification advanced glycation endproducts (AGEs), which will modify lung function during aging. Due to the intrinsic fluorescence of AGEs, this parameter is often used as a non-invasive tool to analyze the “biological age” of patients. Hofmann et al. investigated the AGE modification of collagen of veins from patients undergoing cardiac surgery. They observed that increased modification of collagen leads to reduced extractability. AGE autofluorescence of vein collagen is linked to vessel function (pulse wave velocity) and skin-AGE autofluorescence. Therefore, the noninvasive analysis of the skin autofluorescence using an AGE-reader may directly reflect vessel function as well as vessel age. Franklin Rosenfeld concentrates in his review on oxidative stress in the cardiovascular system. It is generally believed that oxidative stress is the major cause of ischemic reperfusion injury during cardiac operations. Therefore, many groups used different therapies to modify/reduce oxidative stress in surgery with variable results. Future research is still needed to clarify the role of reactive oxygen species in cardiac surgery, especially with old patients. Increased body weight is often associated with age related dysfunctions like heart failure. Niemann et al. therefore investigated the age and obesity-associated regulatory changes of the AMP-dependent protein kinase (AMPK) as the major regulatory protein for the cellular metabolism in right atrial tissue. They identified a complex regulation of this kinase with LKB1 kinase as the major upstream regulator of AMPK. Angelo Scuteri opens this field into a geriatric view. He mentioned especially an important crosstalk between arterial and brain aging. Depending on the hypothesis that prevention is possible in geriatric patients at any age, a shift from traditional cardiovascular risk factors to arterial aging and a re-definition of clinical outcomes for older subjects should be considered. Hettwer et al. identified in a transgenic mouse model a link between dispersal of the neuromuscular junction caused by elevated agrin degradation and the rapid onset of sarcopenia. The elevated levels of a C-terminal agrin fragment as a biomarker of this defect was also seen in a subset of human patients with sarcopenia. This subgroup of patients was further characterized by Drey et al. from the same working group. Sarcopenia can be prevented to some extent by physical exercise. Savela et al. analyzed the effect of low, moderate and high physical activities in a cohort of 782 men on leucocyte telomere length (LTL). From their findings they could conclude that both low and high physical activities are in the long-term associated with factors shortening LTL. Pitkälä et al. summarized the effect of physical exercise in a systematic review on 20 randomized controlled trials.
7
These studies show that intensive physical rehabilitation may be beneficial and may even improve the physical functioning of the frailest patients such as those with dementia. The idea that prevention primarily causes some damage, which in turn leads to an increased defense is summarized in the last two papers. Demirovic especially mentioned that is important to understand the stress profile of cells and organisms to understand changes in the outcome of preventive actions. Calabrese summarizes the theoretical model of a hormetic dose response upon low stress as a mechanism to increase health at old age as well as life-span. Inspiring discussions during the Halle meeting showed that these kinds of arenas are needed. These meetings are significant in introducing people from different fields, to cultivate discussions and ideas, and to generate research cooperation. References Afilalo, J., Duque, G., Steele, R., Jukema, J.W., de Craen, A.J., Eisenberg, M.J., 2008. Statins for secondary prevention in elderly patients: a hierarchical Bayesian meta-analysis. J. Am. Coll. Cardiol. 51, 37–45. AGS, 2011. Developed by the Panel on Prevention of Falls in Older Persons, American Geriatrics Society and British Geriatrics Society, 2011. Summary of the Updated American Geriatrics Society/British Geriatrics Society clinical practice guideline for prevention of falls in older persons. J. Am. Geriatr. Soc. 59, 148–157. Guyatt, G.H., Sackett, D.L., Cook, D.J., 1994. Users' guides to the medical literature. II. How to use an article about therapy or prevention. B. What were the results and will they help me in caring for my patients? Evidence-based Medicine Working Group. JAMA 271, 59–63. Lakatta, E., 2002. Age-associated cardiovascular changes in health: impact on cardiovascular disease in older persons. Heart Fail. Rev. 7, 29–49. Liu, C.J., Latham, N.K., 2009. Progressive resistance strength training for improving physical function in older adults. Cochrane Database Syst. Rev. CD002759. Musini, V.M., Tejani, A.M., Bassett, K., Wright, J.M., 2009. Pharmacotherapy for hypertension in the elderly. Cochrane Database Syst. Rev. CD000028. Roberts, C.G., Guallar, E., Rodriguez, A., 2007. Efficacy and safety of statin monotherapy in older adults: a meta-analysis. J. Gerontol. A Biol. Sci. Med. Sci. 62, 879–887.
Andreas Simm University Hospital Halle (Saale), Ernst-Grube Str. 40, D-06120 Halle (Saale), Germany Corresponding author. E-mail address: [email protected]. Kaisu H. Pitkälä Department of General Practice, University of Helsinki and Unit of Primary Health Care, Helsinki University Central Hospital, PO Box 20, 00029 University of Helsinki, Finland
Contents lists available at SciVerse ScienceDirect
Experimental Gerontology journal homepage: www.elsevier.com/locate/expgero
Editorial
Prevention and intervention It is well known that age is a major risk factor for many degenerative diseases. There are several theories related to aging and its degenerative processes. The aging process is, however, mostly driven by the lifelong accumulation of stochastic forms of damage (e.g. oxidation or glycation of the macromolecules). This damage modifies the tissue and, depending on the tissue involved, might be construed as specific risk factors for diseases. This was mentioned by Ed Lakatta (2002) as: “age-associated changes in cardiac and vascular properties alter the substrate upon which cardiovascular disease is superimposed”. On the other hand, a long life expectancy is driven by enhanced repair systems of damage. In light of this view, diseases may be the late outcome of a lifelong damaging process in combination with reduced repair capacities. Therefore, prevention is the only possibility to avoid the early occurrence of degenerative diseases. Preventive medicine refers to actions taken to prevent diseases or injuries rather than curing them. Prevention aims to promote health and it contrasts in methods with curative or palliative medicine. Primary prevention strategies intend to avoid the development of disease at very early stages because often the roots of old age diseases are in childhood or in middle-age. Secondary prevention strategies attempt to treat an existing disease in its early stages before it results in significant morbidity or complications. Treatment of cardiovascular risk factors in diabetes to prevent morbidity is a typical example of secondary prevention. Treatments in tertiary prevention aim to reduce the negative impact of an established disease by restoring function and reducing disease-related complications. Treatment of stroke patient's atrial fibrillation with anticoagulant is a typical example of tertiary prevention. Primary prevention strategies – such as physical exercise – can be beneficial until very old age. However, prevention in old age can often be defined as secondary or tertiary prevention. In old age secondary prevention strategies aim to prevent geriatric syndromes such as cardiovascular diseases, cognitive decline, frailty or falls. Tertiary prevention aims to restore functioning, autonomy and quality-of-life among those already suffering from geriatric syndromes. Intervention studies are used in clinical medicine to test which preventive and treatment strategies are beneficial. Evidence-based medicine considers rigorously performed randomized, controlled clinical trials and their meta-analyses as the top level of evidence on effectiveness of treatment. There is growing body of evidence that various preventive strategies are highly effective in very old age: for example exercise in improving mobility limitations (Liu and Latham, 2009), antihypertensives in preventing cardiovascular morbidity (Musini et al., 2009), statins in primary (Roberts et al., 2007) and secondary prevention for vascular diseases (Afilalo et al, 2008), or various strategies in preventing falls (AGS, 2011). However, we have to be highly aware in which kind of patient or target group these treatments have been tested and to which patient group we ought to implement these treatments (Guyatt et al., 1994). 0531-5565/$ – see front matter © 2012 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.exger.2012.11.002
Still, there are large gaps in our knowledge, especially concerning the frailest and oldest-old: how to help them avoid further complications? How did their geriatric syndromes develop? Especially we know too little about dementia. The dilemma exists: are we too late in old age to prevention? Should we start earlier and how? Many age-related diseases take decades to develop, and we still know too little about the mechanisms behind them. Clinical studies can only test hypotheses that are created in basic science. We need more cooperation between basic scientists, especially biogerontologists, and clinical scientists. In addition, we need translational medical scientists. Translational medicine is research facilitating the translation of findings from basic science to practical applications that enhance human health and well-being. The Halle international meeting 2011 “Prevention and intervention: from molecular biology to clinical perspectives” aimed to gather together and enhance communication among gerontologists working on mechanisms of aging, translational scientists and geriatricians. The keynote speaker and Schober-prize winner, Kaisu Pitkälä from Finland, gave an overview of what kind of evidence exists on preventive strategies in old age populations and what kinds of gaps there are in our knowledge concerning this topic. This issue of Experimental Gerontology gives an overview of the topics presented and the issues discussed in that meeting. Therefore, there are articles on basic science and translational research as well as on clinical medicine. The articles in this issue aim to bridge gaps between, e.g. cardiovascular risk factors to cardiovascular aging process and diseases, and they shed light on mechanisms behind development of sarcopenia and possibilities to prevent it. Using experimental settings like cell cultures or animal models, mechanisms can be identified and investigated which can be further proven in humans. Conserved mechanisms between species can be used to develop biomarkers of aging, which, at the end, may be useful to test the effectiveness of preventive actions. In this regard, Büchner et al. investigated the effect of an unhealthy (fructose and LDL rich) diet and ultrafine carbon black particles (ufCB, as an example of air pollution) on cardiovascular cells. Interestingly, fructose and LDL enriched media induce age related cellular changes like cardiomyocyte hypertrophy, smooth muscle cell proliferation and senescence in endothelial cells. UfCB induces oxidative stress, inhibits telomerase activity and induces cellular senescence in endothelial cells. This indicates the direct impact of the environment on cellular aging. Whereas in mammalians, cellular senescence seems to be important for the lifespan of the organism, Graf et al. showed in contrast, that this is not true for all species. In the model of the short-lived killifish Nothobranchius furzeri, known markers for cellular senescence do not correlate with the age of the fish. Furthermore, the authors cannot detect replicative senescence in primary cell culture models. Another mechanism of aging is the accumulation of glycated proteins in the extracellular matrix of tissues.
Editorial
Indeed, Rolewska et al. showed in the aging mouse lung model, that the fibrillar collagen of the mouse lung tissue displayed a lower enzymatic solubility and increased the amount of the post-translational modification advanced glycation endproducts (AGEs), which will modify lung function during aging. Due to the intrinsic fluorescence of AGEs, this parameter is often used as a non-invasive tool to analyze the “biological age” of patients. Hofmann et al. investigated the AGE modification of collagen of veins from patients undergoing cardiac surgery. They observed that increased modification of collagen leads to reduced extractability. AGE autofluorescence of vein collagen is linked to vessel function (pulse wave velocity) and skin-AGE autofluorescence. Therefore, the noninvasive analysis of the skin autofluorescence using an AGE-reader may directly reflect vessel function as well as vessel age. Franklin Rosenfeld concentrates in his review on oxidative stress in the cardiovascular system. It is generally believed that oxidative stress is the major cause of ischemic reperfusion injury during cardiac operations. Therefore, many groups used different therapies to modify/reduce oxidative stress in surgery with variable results. Future research is still needed to clarify the role of reactive oxygen species in cardiac surgery, especially with old patients. Increased body weight is often associated with age related dysfunctions like heart failure. Niemann et al. therefore investigated the age and obesity-associated regulatory changes of the AMP-dependent protein kinase (AMPK) as the major regulatory protein for the cellular metabolism in right atrial tissue. They identified a complex regulation of this kinase with LKB1 kinase as the major upstream regulator of AMPK. Angelo Scuteri opens this field into a geriatric view. He mentioned especially an important crosstalk between arterial and brain aging. Depending on the hypothesis that prevention is possible in geriatric patients at any age, a shift from traditional cardiovascular risk factors to arterial aging and a re-definition of clinical outcomes for older subjects should be considered. Hettwer et al. identified in a transgenic mouse model a link between dispersal of the neuromuscular junction caused by elevated agrin degradation and the rapid onset of sarcopenia. The elevated levels of a C-terminal agrin fragment as a biomarker of this defect was also seen in a subset of human patients with sarcopenia. This subgroup of patients was further characterized by Drey et al. from the same working group. Sarcopenia can be prevented to some extent by physical exercise. Savela et al. analyzed the effect of low, moderate and high physical activities in a cohort of 782 men on leucocyte telomere length (LTL). From their findings they could conclude that both low and high physical activities are in the long-term associated with factors shortening LTL. Pitkälä et al. summarized the effect of physical exercise in a systematic review on 20 randomized controlled trials.
7
These studies show that intensive physical rehabilitation may be beneficial and may even improve the physical functioning of the frailest patients such as those with dementia. The idea that prevention primarily causes some damage, which in turn leads to an increased defense is summarized in the last two papers. Demirovic especially mentioned that is important to understand the stress profile of cells and organisms to understand changes in the outcome of preventive actions. Calabrese summarizes the theoretical model of a hormetic dose response upon low stress as a mechanism to increase health at old age as well as life-span. Inspiring discussions during the Halle meeting showed that these kinds of arenas are needed. These meetings are significant in introducing people from different fields, to cultivate discussions and ideas, and to generate research cooperation. References Afilalo, J., Duque, G., Steele, R., Jukema, J.W., de Craen, A.J., Eisenberg, M.J., 2008. Statins for secondary prevention in elderly patients: a hierarchical Bayesian meta-analysis. J. Am. Coll. Cardiol. 51, 37–45. AGS, 2011. Developed by the Panel on Prevention of Falls in Older Persons, American Geriatrics Society and British Geriatrics Society, 2011. Summary of the Updated American Geriatrics Society/British Geriatrics Society clinical practice guideline for prevention of falls in older persons. J. Am. Geriatr. Soc. 59, 148–157. Guyatt, G.H., Sackett, D.L., Cook, D.J., 1994. Users' guides to the medical literature. II. How to use an article about therapy or prevention. B. What were the results and will they help me in caring for my patients? Evidence-based Medicine Working Group. JAMA 271, 59–63. Lakatta, E., 2002. Age-associated cardiovascular changes in health: impact on cardiovascular disease in older persons. Heart Fail. Rev. 7, 29–49. Liu, C.J., Latham, N.K., 2009. Progressive resistance strength training for improving physical function in older adults. Cochrane Database Syst. Rev. CD002759. Musini, V.M., Tejani, A.M., Bassett, K., Wright, J.M., 2009. Pharmacotherapy for hypertension in the elderly. Cochrane Database Syst. Rev. CD000028. Roberts, C.G., Guallar, E., Rodriguez, A., 2007. Efficacy and safety of statin monotherapy in older adults: a meta-analysis. J. Gerontol. A Biol. Sci. Med. Sci. 62, 879–887.
Andreas Simm University Hospital Halle (Saale), Ernst-Grube Str. 40, D-06120 Halle (Saale), Germany Corresponding author. E-mail address: [email protected]. Kaisu H. Pitkälä Department of General Practice, University of Helsinki and Unit of Primary Health Care, Helsinki University Central Hospital, PO Box 20, 00029 University of Helsinki, Finland