Immune outcomes are key mediators of many health benefits of exercise and are determined by exercise type,dose(frequency/duration,intensity),and individual characteristics.Similarly,reduced availability of ambient oxy...Immune outcomes are key mediators of many health benefits of exercise and are determined by exercise type,dose(frequency/duration,intensity),and individual characteristics.Similarly,reduced availability of ambient oxygen(hypoxia)modulates immune functions depending on the hypoxic dose and the individual capacity to respond to hypoxia.How combined exercise and hypoxia(e.g.,high-altitude training)sculpts immune responses is not well understood,although such combinations are becoming increasingly popular.Therefore,in this paper,we summarize the impact on immune responses of exercise and of hypoxia,both independently and together,with a focus on specialized cells in the innate and adaptive immune system.We review the regulation of the immune system by tissue oxygen levels and the overlapping and distinct immune responses related to exercise and hypoxia,then we discuss how they may be modulated by nutritional strategies.Mitochondrial,antioxidant,and anti-inflammatory mechanisms underlie many of the adaptations that can lead to improved cellular metabolism,resilience,and overall immune functions by regulating the survival,differentiation,activation,and migration of immune cells.This review shows that exercise and hypoxia can impair or complement/synergize with each other while regulating immune system functions.Appropriate acclimatization,training,and nutritional strategies can be used to avoid risks and tap into the synergistic potentials of the poorly studied immune consequences of exercising in a hypoxic state.展开更多
1.Aging and exercise Aging is associated with the decline of cellular,tissue,and systemic functions and is characterized by at least 7 highly interdependent molecular pillars of aging1(Fig.1).Besides compromised genet...1.Aging and exercise Aging is associated with the decline of cellular,tissue,and systemic functions and is characterized by at least 7 highly interdependent molecular pillars of aging1(Fig.1).Besides compromised genetic functions(telomer shortening and epigenetic dysregulation),metabolic efficiency(impaired mitochondrial functions and nutrient sensing),and cellular stress responses deteriorate.Consequential disruption of normal protein regulation(proteostasis)in combination with impaired cellular waste clearance leads to the accumulation of macromolecular damage(and in some cases to specific protein aggregation pathologies,like in Alzheimer’s dementia brains).展开更多
Regular physical activity(PA)promotes healthy aging,and activities aiming to increase muscular strength(i.e.,resistance exercise(RE))are important PA modalities for achieving health benefits.Previous meta-analyses dem...Regular physical activity(PA)promotes healthy aging,and activities aiming to increase muscular strength(i.e.,resistance exercise(RE))are important PA modalities for achieving health benefits.Previous meta-analyses demonstrated that both RE^(1) and muscular strength^(2) were associated with mortality benefits,even when RE was performed above the PA targets recommended by current guidelines^(1,3).展开更多
Hypoxia is increasingly recognized as an important physiological driving force.A specific transcriptional program,induced by a decrease in oxygen(O2)availability,for example,inspiratory hypoxia at high altitude,allows...Hypoxia is increasingly recognized as an important physiological driving force.A specific transcriptional program,induced by a decrease in oxygen(O2)availability,for example,inspiratory hypoxia at high altitude,allows cells to adapt to lower O2 and limited energy metabolism.This transcriptional program is partly controlled by and partly independent of hypoxia-inducible factors.Remarkably,this same transcriptional program is stimulated in the brain by extensive motor-cognitive exercise,leading to a relative decrease in O2 supply,compared to the acutely augmented O2 requirement.We have coined the term“functional hypoxia”for this important demand-responsive,relative reduction in O2 availability.Functional hypoxia seems to be critical for enduring adaptation to higher physiological challenge that includes substantial“brain hardware upgrade,”underlying advanced performance.Hypoxia-induced erythropoietin expression in the brain likely plays a decisive role in these processes,which can be imitated by recombinant human erythropoietin treatment.This article review presents hints of how inspiratory O2 manipulations can potentially contribute to enhanced brain function.It thereby provides the ground for exploiting moderate inspiratory plus functional hypoxia to treat individuals with brain disease.Finally,it sketches a planned multistep pilot study in healthy volunteers and first patients,about to start,aiming at improved performance upon motor-cognitive training under inspiratory hypoxia.展开更多
Areas at high-altitude,annually attract millions of tourists,skiers,trekkers,and climbers.If not adequately prepared and not considering certain ascent rules,a considerable proportion of those people will suffer from ...Areas at high-altitude,annually attract millions of tourists,skiers,trekkers,and climbers.If not adequately prepared and not considering certain ascent rules,a considerable proportion of those people will suffer from acute mountain sickness(AMS)or even from life-threatening high-altitude cerebral(HACE)or/and pulmonary edema(HAPE).Reduced inspired oxygen partial pressure with gain in altitude and consequently reduced oxygen availability is primarily responsible for getting sick in this setting.Appropriate acclimatization by slowly raising the hypoxic stimulus(e.g.,slow ascent to high altitude)and/or repeated exposures to altitude or artificial,nor-mobaric hypoxia will largely prevent those illnesses.Understanding physiological mechanisms of acclimatization and pathophysiological mechanisms of high-altitude diseases,knowledge of symptoms and signs,treatment and prevention strategies will largely contribute to the risk reduction and increased safety,success and enjoyment at high altitude.Thus,this review is intended to provide a sound basis for both physicians counseling high-altitude visitors and high-altitude visitors themselves.展开更多
Hypoxia is an essential topic in medical or biological sciences.The main aims of the present study were to examine the most important medical articles(i.e.,the top 100 most cited)on hypoxia.We examine how the Nobel-pr...Hypoxia is an essential topic in medical or biological sciences.The main aims of the present study were to examine the most important medical articles(i.e.,the top 100 most cited)on hypoxia.We examine how the Nobel-prize awarded hypoxia inducible factor(HIF)-pathway discovery in the early 1990s has changed the thematic composition of this body of literature,with a special emphasis on the studies linking hypoxia and cancer.We searched Pubmed for articles with the terms#Hypox,#Altitude,or#Mountain in the title that have been published in biomedical journals and ranked the articles on their number of citations in Web of Science.A second search was performed in all journals for articles related to hypoxia and cancer.Strikingly,only 12 of the top-100 most-cited articles on hypoxia and only 3 articles of the top-100 articles related to cancer were published before 1995.Moreover,only 5 articles from prior 1995 reached 1000 citations,while 27 articles published in 1995 or later were cited more than 1000 times,most of them on the HIF-1 pathway.Eighty percent of the top-100 articles were related to the HIF pathway,while there were no articles on the application of hypoxia either for therapeutic use(i.e.,hypoxic conditioning in patients)or for performance enhancement(i.e.,altitude training in athletes).In conclusion,the early-1990s discovery of the HIF pathway and of its molecular regulation has shifted the focus of hypoxia research towards molecular mechanisms and consequences of tissue hypoxia,most notably in cancer.The importance of studies focusing on clinical and performance applications of systemic hypoxia is relatively lower.展开更多
Hypoxia is more and more perceived as pivotal physiological driving force,allowing cells in the brain and elsewhere to acclimate to lowered oxygen(O_(2)),and abridged metabolism.The mediating transcription program is ...Hypoxia is more and more perceived as pivotal physiological driving force,allowing cells in the brain and elsewhere to acclimate to lowered oxygen(O_(2)),and abridged metabolism.The mediating transcription program is induced by inspiratory hypoxia but also by intensive motor-cognitive tasks,provoking a relative decrease in O_(2) in relation to the acutely augmented requirement.We termed this fundamental,demand-dependent drop in O_(2) availability"functional hypoxia."Major players in the hypoxia response are hypoxia-inducible factors(HIFs)and associated prolyl-hydroxylases.HIFs are transcription factors,stabilized by low O_(2) accessibility,and control expression of a multitude of genes.Changes in oxygen,however,can also be sensed via other pathways,among them the thiol-oxidase(2-aminoethanethiol)dioxygenase.Considering the far-reaching biological response to hypoxia,hitherto mostly observed in rodents,we initiated a translational project,combining mild to moderate inspiratory with functional hypoxia.We had identified this combination earlier to benefit motor-cognitive attainment in mice.A total of 20 subjects were included:13 healthy individuals and 7 patients with depression and/or autism spectrum disorder.Here,we show that motor-cognitive training under inspiratory hypoxia(12%O_(2))for 3.5 h daily over 3 weeks is optimally tolerated.We present first signals of beneficial effects on general well-being,cognitive performance,physical fitness and psychopathology.Erythropoietin in serum increases under hypoxia and flow cytometry analysis of blood reveals several immune cell types to be mildly modulated by hypoxia.To obtain reliable information regarding the"add-on"value of inspiratory on top of functional hypoxia,induced by motor-cognitive training,a single-blind study—with versus without inspiratory hypoxia—is essential and outlined here.展开更多
文摘Immune outcomes are key mediators of many health benefits of exercise and are determined by exercise type,dose(frequency/duration,intensity),and individual characteristics.Similarly,reduced availability of ambient oxygen(hypoxia)modulates immune functions depending on the hypoxic dose and the individual capacity to respond to hypoxia.How combined exercise and hypoxia(e.g.,high-altitude training)sculpts immune responses is not well understood,although such combinations are becoming increasingly popular.Therefore,in this paper,we summarize the impact on immune responses of exercise and of hypoxia,both independently and together,with a focus on specialized cells in the innate and adaptive immune system.We review the regulation of the immune system by tissue oxygen levels and the overlapping and distinct immune responses related to exercise and hypoxia,then we discuss how they may be modulated by nutritional strategies.Mitochondrial,antioxidant,and anti-inflammatory mechanisms underlie many of the adaptations that can lead to improved cellular metabolism,resilience,and overall immune functions by regulating the survival,differentiation,activation,and migration of immune cells.This review shows that exercise and hypoxia can impair or complement/synergize with each other while regulating immune system functions.Appropriate acclimatization,training,and nutritional strategies can be used to avoid risks and tap into the synergistic potentials of the poorly studied immune consequences of exercising in a hypoxic state.
文摘1.Aging and exercise Aging is associated with the decline of cellular,tissue,and systemic functions and is characterized by at least 7 highly interdependent molecular pillars of aging1(Fig.1).Besides compromised genetic functions(telomer shortening and epigenetic dysregulation),metabolic efficiency(impaired mitochondrial functions and nutrient sensing),and cellular stress responses deteriorate.Consequential disruption of normal protein regulation(proteostasis)in combination with impaired cellular waste clearance leads to the accumulation of macromolecular damage(and in some cases to specific protein aggregation pathologies,like in Alzheimer’s dementia brains).
文摘Regular physical activity(PA)promotes healthy aging,and activities aiming to increase muscular strength(i.e.,resistance exercise(RE))are important PA modalities for achieving health benefits.Previous meta-analyses demonstrated that both RE^(1) and muscular strength^(2) were associated with mortality benefits,even when RE was performed above the PA targets recommended by current guidelines^(1,3).
基金supported by the Max Planck Society,the Max Planck Förderstiftung,the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation),via DFG-Center for Nanoscale Microscopy&Molecular Physiology of the Brain(CNMPB)and DFG-TRR 274/12020–408885537.
文摘Hypoxia is increasingly recognized as an important physiological driving force.A specific transcriptional program,induced by a decrease in oxygen(O2)availability,for example,inspiratory hypoxia at high altitude,allows cells to adapt to lower O2 and limited energy metabolism.This transcriptional program is partly controlled by and partly independent of hypoxia-inducible factors.Remarkably,this same transcriptional program is stimulated in the brain by extensive motor-cognitive exercise,leading to a relative decrease in O2 supply,compared to the acutely augmented O2 requirement.We have coined the term“functional hypoxia”for this important demand-responsive,relative reduction in O2 availability.Functional hypoxia seems to be critical for enduring adaptation to higher physiological challenge that includes substantial“brain hardware upgrade,”underlying advanced performance.Hypoxia-induced erythropoietin expression in the brain likely plays a decisive role in these processes,which can be imitated by recombinant human erythropoietin treatment.This article review presents hints of how inspiratory O2 manipulations can potentially contribute to enhanced brain function.It thereby provides the ground for exploiting moderate inspiratory plus functional hypoxia to treat individuals with brain disease.Finally,it sketches a planned multistep pilot study in healthy volunteers and first patients,about to start,aiming at improved performance upon motor-cognitive training under inspiratory hypoxia.
文摘Areas at high-altitude,annually attract millions of tourists,skiers,trekkers,and climbers.If not adequately prepared and not considering certain ascent rules,a considerable proportion of those people will suffer from acute mountain sickness(AMS)or even from life-threatening high-altitude cerebral(HACE)or/and pulmonary edema(HAPE).Reduced inspired oxygen partial pressure with gain in altitude and consequently reduced oxygen availability is primarily responsible for getting sick in this setting.Appropriate acclimatization by slowly raising the hypoxic stimulus(e.g.,slow ascent to high altitude)and/or repeated exposures to altitude or artificial,nor-mobaric hypoxia will largely prevent those illnesses.Understanding physiological mechanisms of acclimatization and pathophysiological mechanisms of high-altitude diseases,knowledge of symptoms and signs,treatment and prevention strategies will largely contribute to the risk reduction and increased safety,success and enjoyment at high altitude.Thus,this review is intended to provide a sound basis for both physicians counseling high-altitude visitors and high-altitude visitors themselves.
文摘Hypoxia is an essential topic in medical or biological sciences.The main aims of the present study were to examine the most important medical articles(i.e.,the top 100 most cited)on hypoxia.We examine how the Nobel-prize awarded hypoxia inducible factor(HIF)-pathway discovery in the early 1990s has changed the thematic composition of this body of literature,with a special emphasis on the studies linking hypoxia and cancer.We searched Pubmed for articles with the terms#Hypox,#Altitude,or#Mountain in the title that have been published in biomedical journals and ranked the articles on their number of citations in Web of Science.A second search was performed in all journals for articles related to hypoxia and cancer.Strikingly,only 12 of the top-100 most-cited articles on hypoxia and only 3 articles of the top-100 articles related to cancer were published before 1995.Moreover,only 5 articles from prior 1995 reached 1000 citations,while 27 articles published in 1995 or later were cited more than 1000 times,most of them on the HIF-1 pathway.Eighty percent of the top-100 articles were related to the HIF pathway,while there were no articles on the application of hypoxia either for therapeutic use(i.e.,hypoxic conditioning in patients)or for performance enhancement(i.e.,altitude training in athletes).In conclusion,the early-1990s discovery of the HIF pathway and of its molecular regulation has shifted the focus of hypoxia research towards molecular mechanisms and consequences of tissue hypoxia,most notably in cancer.The importance of studies focusing on clinical and performance applications of systemic hypoxia is relatively lower.
基金ERC Advanced Grant acronym BREPOCI,Grant/Award Number:101054369ALTIBRAIN,Grant/Award Number:101043416DFG,Grant/Award Number:TRR-274/12020-408885537。
文摘Hypoxia is more and more perceived as pivotal physiological driving force,allowing cells in the brain and elsewhere to acclimate to lowered oxygen(O_(2)),and abridged metabolism.The mediating transcription program is induced by inspiratory hypoxia but also by intensive motor-cognitive tasks,provoking a relative decrease in O_(2) in relation to the acutely augmented requirement.We termed this fundamental,demand-dependent drop in O_(2) availability"functional hypoxia."Major players in the hypoxia response are hypoxia-inducible factors(HIFs)and associated prolyl-hydroxylases.HIFs are transcription factors,stabilized by low O_(2) accessibility,and control expression of a multitude of genes.Changes in oxygen,however,can also be sensed via other pathways,among them the thiol-oxidase(2-aminoethanethiol)dioxygenase.Considering the far-reaching biological response to hypoxia,hitherto mostly observed in rodents,we initiated a translational project,combining mild to moderate inspiratory with functional hypoxia.We had identified this combination earlier to benefit motor-cognitive attainment in mice.A total of 20 subjects were included:13 healthy individuals and 7 patients with depression and/or autism spectrum disorder.Here,we show that motor-cognitive training under inspiratory hypoxia(12%O_(2))for 3.5 h daily over 3 weeks is optimally tolerated.We present first signals of beneficial effects on general well-being,cognitive performance,physical fitness and psychopathology.Erythropoietin in serum increases under hypoxia and flow cytometry analysis of blood reveals several immune cell types to be mildly modulated by hypoxia.To obtain reliable information regarding the"add-on"value of inspiratory on top of functional hypoxia,induced by motor-cognitive training,a single-blind study—with versus without inspiratory hypoxia—is essential and outlined here.
