Aging as a Consequence of the Adaptation–Maladaptation Dilemma

In aging, the organism is unable to counteract certain harmful influences over its lifetime which leads to progressive dysfunction and eventually death, thus delineating aging as one failed process of adaptation to a set of aging stimuli. A central problem in understanding aging is hence to explain why the organism cannot adapt to these aging stimuli. The adaptation–maladaptation theory of aging proposes that in aging adaptation processes such as adaptive transcription, epigenetic remodeling, and metabolic plasticity drive dysfunction themselves over time (maladaptation) and thereby cause aging‐related disorders such as cancer and metabolic dysregulation. The central dilemma of aging is thus that the set of adaptation mechanisms that the body uses to deal with internal and external stressors acts as a stressor itself and cannot be effectively counteracted. The only available option for the organism to decrease maladaptation may be a program to progressively reduce the output of adaptive cascades (e.g., via genomic methylation) which then leads to reduced physiological adaptation capacity and syndromes like frailty, immunosenescence, and cognitive decline. The adaptation–maladaptation dilemma of aging entails that certain biological mechanisms can simultaneously protect against aging as well as drive aging. The key to longevity may lie in uncoupling adaptation from maladaptation.


Introduction
Biological organisms are self-regulating systems that constantly adapt to their environments.This ability for adaptation is tightly linked to the organism's survival.In aging, the organism is unable to counteract the negative effects of certain aging stimuli, defined as all influences which can drive the aging process and which can be endogenous (e.g., oxidative stress, DNA repair errors, transcriptional variability, molecular hyperfunction) as well as exogenous (e.g., radiation damage, infections, environmental conditions that induce stress).This leads to progressive DOI: 10.1002/adbi.202300654organismal dysfunction and eventually death.Aging can thus be conceptualized as one overarching failed adaptation process in response to a set of aging stimuli.As the body possesses many highly effective adaptation mechanisms to deal with stressors, one of the central problems in understanding aging is to explain why this adaptation failure occurs.

The Adaptation-Maladaptation Dilemma in Aging
Is there something unique about the set of aging stimuli compared to those stimuli that can be successfully adapted to?The adaptation-maladaptation framework of aging posits that aging is the result of maladaptation and a "recursion barrier" in which the adaptation mechanisms that normally protect the organism from dysfunction through beneficial adaptation drive maladaptation themselves [1] (Figure 1) and have side effects that cannot be countered by adaptive mechanisms.This conundrum has previously been termed the adaptation-maladaptation dilemma. [1]In this framework, adaptation, and maladaptation are defined as processes in relation to the individual organism as opposed to evolutionary processes.Adaptation describes the goal-controlled restructuring of a system to match physiology to changing demands (e.g., learning and memory, muscle hypertrophy, adaptive immunity).Maladaptation refers to a process in which the activation of adaptive mechanisms leads to an overall negative influence on organism physiology such as in oncogenesis, hypertensive cardiovascular remodeling, and autoimmunity.
The body hence cannot protect itself from its own adaptation mechanisms or, phrased differently, the set of adaptive mechanisms cannot adapt to itself.The mechanisms that counter external or internal stressors act as stressors themselves.One fundamental component of aging is a continuous increase of maladaptation and its consequences over the lifetime (Figure 2A).Consequently, one way to counter chronic maladaptation might be to reduce the output of these adaptive cascades over time via an aging program (Figure 2B), thereby however creating the side-effect of decreased beneficial adaptation capacity and an increased susceptibility to stressors.Thus, aging might broadly have two components, one nonprogrammed (i.e., maladaptation) and one programmed (i.e., genetic programs to progressively ).The body's adaptation mechanisms, such as adaptive transcription, stimulus-dependent epigenetic remodeling, and metabolic plasticity, simultaneously implement beneficial adaptive functions (e.g., learning and memory, muscle anabolism, adaptive immunity) as well as maladaptive phenotypes (e.g., cancer, autoimmunity, type 2 diabetes).This duality delineates the adaptation-maladaptation dilemma and presents the organism with a fundamental problem: enable high activity of adaptation cascades and increase fitness but also shorten lifespan due to diseases such as cancer or decrease adaptive fitness but also decrease maladaptive disease risk and increase lifespan.
reduce the activity of adaptive cascades to avoid maladaptation).In the end, the organism has to balance the negative side effects of adaptive mechanisms with their essential physiological functions and calibrate their activity over the lifetime.The central problem for the organism is hence that the set of its adaptation mechanisms overlaps with or is contained within the set of aging stimuli and that in aging the ratio of adaptation to maladaptation always decreases, one way or the other. [1]Aging might thus at least partly be driven by an inability to solve the adaptationmaladaptation dilemma and the framework describing this hypothesis is termed the adaptation-maladaptation theory of aging (AM-theory).
Parts of this framework are reminiscent of hyperfunction theory [9] in that it posits that the elevated function of certain molecular cascades is an important driver in age-related diseases.In AM theory, the important cascades are those that drive adapta-tion, especially those that can implement long-term remodeling processes and can thus cause long-term damage.Elevated activity of adaptation mechanisms and subsequent dysfunctional remodeling can also be caused by external stimuli (e.g., stress) and would thus explain the modulation of the aging process by environmental factors.In order to counteract increasing maladaptation, the body might have evolved dedicated programs to progressively reduce the effects of maladaptation.Perhaps the progressive changes in methylation patterns that characterize aging and build the basis for several epigenetic aging clocks [10] implement a reduction in adaptive functionality to protect the organism from maladaptation.Thus, in aging, the organism would have to balance the two negative processes of maladaptive function with decreases in beneficial adaptation capacity and resulting increased negative effects from other aging stimuli.It is possible that in different individuals, this choice is made differently (e.g., some people die of cancer (hyperadaptation) while others die of neurodegeneration (hypoadaptation)).It is interesting to note that neurodegenerative diseases and cancer have an inverse correlation to each other, [11] thus implying that in some organisms the choice might be made for higher adaptive capacity but higher cancer risk, while in others it might be made for lower adaptive capacity and lower cancer risk.Aging as a two-component process with increasing maladaptation necessitating an aging program to decrease adaptative function.A), Increasing maladaptation over time leads to increased incidence of hyperadaptive age-related disorders (e.g., cancer, autoimmunity, atherosclerosis, type 2 diabetes) and constitutes the nonprogrammed component of aging.B), In order to counteract maladaptation the body might implement an aging program (e.g., through genomic methylation) which decreases adaptation mechanisms in a body-wide manner.This causes a reduction in maladaptation at the cost of also reducing many physiological adaptation phenotypes and leads to hypoadaptive symptom complexes such as dementia, sarcopenia, and immunosenescence.

Molecular Pathways Mediating the Adaptation-Maladaptation Dilemma of Aging
At the molecular level, several adaptation regulators have been implicated in maladaptation.CREB and its co-regulators such as CRTC and CBP are central regulators of stimulusdependent cellular plasticity (Figure 3A) and important for memory formation, [12] metabolic regulation, [13] immune function, [14] muscle regeneration [15] and plasticity, [16] skin physiology, [17] bone physiology, [18] cardiovascular function [19] and developmental processes. [20]Yet, they are also involved in cancer progression, [21] autoimmunity, [22] depression [23] and metabolic dysfunction. [24]ncreasing CREB levels in the brain leads to enhancements in memory performance [25] but also maladaptive circuit remodeling, hyperexcitability, and neuronal cell death. [26]In the aged rodent brain, a decrease in the levels and activation of CREB and CBP have been reported when compared to young animals [27] (one study showed increased CREB phosphorylation levels with age but a decreased induction after stimulation [28] ), suggesting a possible compensatory downregulation.Exogenously increasing CREB levels in the aged brain rescues age-related memory performance. [29]Overexpressing the CREB coregulator CRTC2 , and Myc couple stimulation to cellular plasticity in both adaptive processes (e.g., learning and memory) and maladaptive ones (e.g., cancer).B), Top: Reducing CREB in C. elegans leads to a reduction in memory performance (a major hallmark of aging) but an increase in lifespan.Bottom: Reduction of the adaptive transcription factor Myc in mice leads to reduced homeostasis and accelerated aging but also to decreased cancer incidence and an increased lifespan.C), Inducible DNA damage and repair as an example of the adaptation-maladaptation dilemma.Neuronal activity induces Npas4, a neuroprotective gene important for neural plasticity, via DNA double-strand breaks (DSBs).Npas4 in turn complexes with NuA4 to repair DSBs.Similarly, BDNF induces base-excision repair genes in neurons.The induction of a beneficial adaptation mechanism is hence coupled to directed DNA damage and its repair.Hypothetically, a dysbalancing in these adaptive damage-repair loops could lead to an overtaking of maladaptive genomic damage and aging-related dysfunction.
in muscle cells leads to an anabolic state and enhanced exercise capacity. [16]n C. elegans, CREB inactivation was shown to decrease memory [30] but to increase lifespan [31] (one study did not observe lifespan effects [30a] ) (Figure 3B).Similarly, reduction of the CREB co-activator CRTC increases lifespan. [31]However, in increased temperatures, deletion of CREB in sensory neurons has a deleterious effect on lifespan in C. elegans. [32]The complex role of CREB signaling hence illustrates the conundrum of decreasing adaptive fitness and increasing lifespan as a consequence of the adaptation-maladaptation dilemma.In mice with a diverse genetic background, caloric restriction enhances lifespan but at the cost of memory performance. [33]Interventions that impair memory formation, a major hallmark of aging in animals, thus also increase lifespan, thereby seeming to counteract aging.Reductions in the levels of the adaptive transcription factor Myc (Figure 3A), which in humans is induced in skeletal muscles after exercise [34] and whose overexpression in rodent muscles leads to enhanced protein synthesis, [35] lead to similar observations, namely a re-duction in many physiological homeostatic functions but also a reduced cancer incidence (i.e., reduced maladaptation) and an increased lifespan [36] (Figure 3B).Interestingly, in humans, Myc gene methylation increases with age, [37] hinting at the possibility that methylation-based silencing of Myc is part of an aging program to reduce maladaptation.36a] In fruit flies, the acetyltransferase chameau increases adaptability under starvation at the cost of reduced longevity, thus confirming an inverse correlation between acute adaptation capacity and lifespan. [38]lso interesting in this regard are observations of an induction of cancer-like metabolic programs in neurons after synaptic stimulation [39] and in muscle fibers during hypertrophy, [40] but rather than neurons and muscle cells using a cancer program, it is probably the case that cancer cells use a universal adaptive metabolic program for their progression.
How can the observations of compromised adaptability but increased lifespan be explained?The animals in these studies are lab animals in which the decrease in memory and other adaptive functions is most likely not survival-limiting because environmental stress is heavily reduced (e.g., lower exposure to infectious agents, no predation risk, ample food supply).Consequently, the reduced maladaptation rate (e.g., lower cancer and lower metabolic dysregulation) might translate to an increased lifespan.It would be predicted that in the wild, with increased stressor exposure, these animals would perform worse and not survive as long.In the context of evolution and the individual, the AM dilemma entails that curbing adaptive responses would be beneficial for some animals (i.e., those that have a hyper-adaptive balance) but, importantly, detrimental to others (e.g., those that have a hypoadaptive state).Perhaps then, organisms, also from an evolutionary perspective, can choose to perish from either a hyperadaptive or a hypoadaptive phenotype.
A subcategory of maladaptation, next to dysfunctional remodeling, is damage induced by adaptation mechanisms which also has been previously outlined. [1]One example is the induction of adaptive genes such as Npas4 and Fos via DNA double-strand breaks (DSBs) [41] (Figure 3C).Environmental enrichment, which induces immediate early genes, [42] is neuroprotective [43] but also leads to the induction of DSBs which is exacerbated by A-beta amyloid. [44]Interestingly, neural activity seems to simultaneously upregulate DNA repair mechanisms, in some cases via the very molecules whose induction depends on DSB formation, such as Npas4 [45] (i.e., Npas4 induction depends on DSB formation while Npas4 itself regulates DSB repair (Figure 3C)).Npas4 is neuroprotective [46] and Npas4-mediated DNA repair has been linked to organismal lifespan in mice. [45]Relatedly, calcineurin has been implicated as a positive regulator of activity-dependent DSB formation [47] and Npas4 induction in neurons [48] and calcineurin inhibition in C. elegans leads to lifespan extension. [49]he transcriptional repressor DREAM has recently been shown to negatively regulate DNA repair mechanisms. [50]In neurons, DREAM negatively regulates immediate early gene induction and memory [51] and its deletion slows brain aging. [52]Thus, it seems that neurons simultaneously upregulate immediate early genes, DSB induction, and DNA repair machinery when activated.A recent study has also demonstrated that many base excision repair genes are bound by CREB in neurons and that treatment with BDNF upregulates transcription of these genes. [53]erhaps then a dysbalancing of these processes could partly explain age-related increases in genomic changes in neurons in humans. [54]If the repair cascades do not work properly, this would lead to a relative overtaking of damaging mechanisms during adaptation and could drive dysfunction.Maybe dysregulated gene expression patterns in aging and subsequent maladaptation are partly caused by genomic changes to regulatory regions as a result of DNA damage from adaptive gene inductions.As another example of potentially negative side-effects from physiological adaptation mechanisms, the activity-dependent gene Arc, which is required for learning and memory, [55] also increases Abeta-amyloid formation in the brain. [56]

Determinants of the Adaptation-Maladaptation Balance
An important problem then is how adaptation and maladaptation are differentially induced by the same molecules.In which context does activation of a molecule such as CREB lead to adaptation and in which case to maladaptation?One important factor might be signaling dynamics.The same molecules can have drastically different downstream effects, depending on their activation patterns such as transient versus sustained time courses. [57]or instance, interleukin 6 (IL-6) is involved in processes both potentially beneficial (e.g., promoting insulin sensitivity, [58] downregulating inflammation [59] ) and harmful (e.g., cancer progression [60] ).It is induced in skeletal muscle by acute exercise [61] and upregulated in blood plasma after exercise. [62]In older individuals, blood baseline IL-6 levels are higher [63] while exercise-mediated IL-6 induction in muscle has been reported to be blunted [64] (although similar inductions between young and aged have been reported [63] ).Interestingly, with chronic exercise, IL-6 baseline levels in the blood decrease. [65]Arc, a memory regulator in the brain that is induced by learning tasks, [55] is elevated at baseline in the rodent hippocampus of cognitively impaired aged animals, and its behavioral induction is blunted. [66]Certain adaptation mediators are hence increased at baseline during aging and their induction by physiological stimulation can be reduced.Beneficial interventions such as exercise can lead to an acute induction but a chronic downregulation of these molecules.This phenotype might be in part explained by a desensitization of adaptive cascades after acute stimulation such as in adaptive transcription in neurons. [67]Dynamics might hence be crucial when it comes to a biological mechanism's role in exerting antior pro-aging effects.Many adaptive transcription mechanisms whose activation is associated with pro-longevity effects [68] are simultaneously associated with aging-related disorders such as cancer and metabolic dysregulation. [69]If we consider that different molecular activation patterns can lead to very different outcomes (e.g., sustained ERK activation drives differentiation while transient activation drives proliferation in certain cells [70] ), we see that signaling dynamics might be an important regulating factor in the adaptation-maladaptation dilemma of aging.

Implications and Predictions of the Adaptation-Maladaptation Theory of Aging
The adaptation-maladaptation hypothesis thus posits that adaptation and maladaptation are intricately linked to each other and that aging is at least partially a consequence of the adaptationmaladaptation dilemma.The only option for the organism to deal with this dilemma might be to balance progressive dysfunctions from nonprogrammed maladaptation with those from programmed adaptation reductions, with progressive decline in the ratio of adaptation to maladaptation and hence aging being inevitable.In the following some implications of this theory are discussed.
First, it explains why certain processes and molecules are implicated in both protection against aging-related decline as well as in driving aging, such as activity of CREB, Fos, and other adaptation genes (see above and previous work [1,69] ).After all, why would the deletion of genes that mediate resilience to stress and increase adaptability (e.g., positive memory regulators) cause an extended lifespan?In AM theory, this is because these processes drive both beneficial adaptation (e.g., learning and memory, adaptive immune function, activity-dependent muscle remodeling) and maladaptation (e.g., cancer, metabolic and cardiovascular remodeling) and in conditions where maladaptation is life-limiting (i.e., many laboratory environments) downregulating these pathways leads to lifespan extension.Thus, there is under most conditions a fundamental trade-off between fitness and lifespan.Adaptation is one of the central determinants of fitness and its reduction leads to many physiological impairments but also to decreased maladaptation and, in the absence of overwhelming stressors, to longer lifespans.In laboratory animals, curbing adaptive processes hence usually leads to enhancements in lifespan because these animals are isolated from stressors.In the wild, many "antiadaptive" longevity interventions might not translate to longer survival.AM theory is hence in line with antagonistic pleiotropy [71] which states that certain gene variants that increase fitness (i.e., adaptation) early on can have detrimental effects in later life (i.e., maladaptation).
Second, AM theory posits that aging has both components that are not programmed (e.g., adaptative hyperfunction, molecular damage from adaptive mechanisms) and programmed (e.g., continuous reduction of plasticity mediators over time).Organisms can die from hypoadaptation (e.g., infectious diseases) or hyperadaptation (e.g., cancer, cardiovascular remodeling).
Third, AM theory links adaptive mechanisms to maladaptation regardless of organizational level (e.g., cellular, tissue, and organism) and is thus scale-independent.It can be applied to cells, tissues, organ systems, and the whole body.For instance, neural circuits in aged animals display a maladaptive response in that the excitation-inhibition balance increases after overstimulation instead of decreasing as in young animals. [72]AM theory could also accommodate the notion that single-celled organisms age, as has been proposed, [73] if they face the AM dilemma.Perhaps aging is then the result of an underlying error in the functional organization of all biological systems.Relatedly, there exist most likely many more biological mechanisms in addition to those mentioned above that mediate the adaptationmaladaptation dilemma.Future research could search for novel mechanisms that implement both adaptation and maladaptation in aging.
Fourth, because of different trade-off choices in the AM dilemma, some proposed longevity interventions might have different effects in different individuals.In individuals with a hypoadaptive phenotype, antiadaptive interventions could perhaps lead to an increased susceptibility to infection, sarcopenia, and dementia among other things, and thus accelerate aging-related dysfunction.
Fifth, it is able to incorporate different theories of aging such as hyperfunction, aging as a program, and damage-related theories of aging.AM theory posits for instance that damage can cause aging in those cases in which beneficial adaptation is insufficient which usually happens later in life and usually due to programmed downregulation of adaptation cascades.It explains that as long as organisms or cells can adapt to and compensate for the damage it does not drive aging-related pathology.
Sixth, it answers the question of why animal bodies across different species would enable or implement the downregulation of beneficial molecules such as CREB that protect it from so many aging effects.It is because these drive maladaptation.This could even extend to the behavioral level.Many elderly organisms develop behavioral patterns that isolate them from stressors.Thus in order to deal with a reduced stress adaptability, organisms retreat and isolate themselves.

Implications for Translational Efforts
The key to longevity might be to raise beneficial adaptation and decrease maladaptation, to thus uncouple the processes of adaptation and maladaptation from each other (i.e., shifting the adaptation-maladaptation balance).This would entail the induction of metaplasticity (i.e., changing the adaptability of the system).Interestingly, well-studied environmental interventions including exercise and environmental enrichment which work via adaptive transcriptional cascades [68] seem to be able to achieve this (Figure 4).Environmental enrichment for instance induces metaplasticity in neurons in the brain [74] and exercise induces enhanced neuronal plasticity [75] and metaplasticity in skeletal muscles, [76] as well as a reduced cancer incidence. [77]These interventions hence lead to increases in adaptation and simultaneous decreases in maladaptation (also see previous work [1] ).
Raising adaptation could also be achieved by transgenic or pharmacological means.Viral overexpression of CREB in the brain has been shown to improve memory in aged rats. [29]Similarly, overexpression of other adaptive signaling molecules in aged animals improves memory performance to young levels, including Dnmt3a2 [78] and CaMKIV. [79]On the pharmacological side, HDAC inhibitors acting via CREB have been demonstrated to increase memory performance [80] and PDE4 inhibition via rolipram, which increases CREB activity, leads to memory enhancement in aged animals. [81]A caveat with these strategies is that they also might increase maladaptation if the dynamics are not chosen correctly (e.g., prolonged CREB overexpression leads to neural circuit maladaptation and neuronal death [26] ).

Considerations and Caveats
AM theory is conceptually related to antagonistic pleiotropy which states that certain genes that have beneficial functions earlier in life can have detrimental functions later in life and hence contribute to aging. [71]The antagonistic pleiotropy framework however does not give a mechanistic insight into how this central tradeoff is mediated nor whether and how it could be modified.AM theory describes the central logical conundrum at the heart of antagonistic pleiotropy, namely that adaptation pathways that counter stressors act as stressors themselves and cannot adapt to themselves.As a result, interventions that increase adaptation and decrease maladaptation as described above can principally counteract aging.
A central problem in AM theory concerns the cause of increasing maladaptation and resulting phenotypes during aging.The rising rate of maladaptation within an organism could be a result of hyperfunction of adaptation mediators (e.g., CREB).Yet, in hyperfunction theory, aging-related dysfunction is posited to be mainly secondary to molecular hyperfunction without a programmed aspect of aging. [9]AM theory in contrast delineates aging as a two-component process, namely nonprogrammed maladaptation and programmed adaptation reductions to counter rising maladaptation.The deficits that increase with age over the lifetime [82] would thus have two origins in AM theory, namely as An interesting problem is the time course of these processes over the life of an organism and how and when they lead to functional impairments (e.g., see life course-based perspectives on aging [83] ).Maladaptation could be present right from the conception of an organism and masked for a while by compensatory mechanisms (e.g., the proposed adaptation reductions) or it could arise at later time points (e.g., after the completion of development).In the latter case, compensatory mechanisms would need to be activated later in the life course to ensure successful aging.A temporal mismatch of the two aging components (i.e., nonprogrammed maladaptation and programmed adaptation reduction) would lead to accelerated aging.
The concept of allostatic load delineates an important modulator of maladaptation, namely environmental stress.Increasing stress and consequently allostatic load would thus increase an organism's maladaptation rate.In line with concepts that proposed allostatic load as a driver for accelerated biological aging and agerelated disease risk, [84] increased allostatic load would decrease the ratio of adaptation to maladaptation in a system and thereby also increase biological age in AM theory.In AM theory, however, allostatic load would not be the only source for maladaptation.Instead, maladaptation is inevitable even from baseline function.
In certain programmatic aging theories, aging is posited to be the result of an activation of developmental processes during adulthood. [85]In the framework of AM theory, development constitutes an adaptation-intensive phase which is why many adaptation processes are heavily activated during this time span.The curbing of adaptive cascades can lead to delayed and altered development and delayed maladaptation, in some cases perhaps even independent of each other.In AM theory, the programmed aspect of aging has a clear purpose, namely to avoid aging-related maladaptation (e.g., cancer, autoimmunity).
As described above, the induction of molecular plasticity regulators in cells is coupled to DNA double-strand breaks in genomic regulatory elements (Figure 3C).Perhaps then, repeated damage induction in these areas and/or a dysbalancing of the dependent DNA repair mechanisms leads to sequence degradation of these elements with a subsequent increase in maladaptation and progression of aging-related diseases.This can be connected to loss of genetic information in the information theory of aging which states that DNA mutations can degrade cellular function through information loss. [86]In the information theory of aging the primary effect is posited to be a loss of cell identity whereas in AM theory the important aspect would be the dysregulation of adaptive responses.Similarly, adaptation processes generally involve epigenetic remodeling [68] and perhaps repeated activation or overactivation of these processes can lead to a degradation of epigenetic marks with subsequent maladaptive process activation.
Adaptation is a process involving many feedback loops and regulation mechanisms.It could be that decreasing adaptive capacities in one pathway increases adaptive capacities in another.
Biological systems display counter efforts to external disturbance and thus usually also to interventions.Due to degeneracy, it could be that interventions that decrease the activity of one adaptation pathway lead to compensatory changes in another one (e.g., downregulation of CREB leads to upregulation of CREM [87] ).The blocking of some adaptive cascades could potentially lead to the upregulation of others and hence correct adaptive dysbalances.Thus, care must be taken when an "adaptation blocker" is applied as this could very well translate to an increase in adaptive capacity in another pathway.For instance, treatment with rapamycin which inhibits mTOR (adaptation mechanism one decrease) increases CREB phosphorylation (adaptation mechanism two increase). [88]A related point concerns the causality of age-dependent downregulation of adaptation cascades.These could be preconfigured genetic programs and potentially connected to the methylation changes that build the basis for aging clocks or these downregulations could be an automatic result of negative feedback loops.For instance, heightened CREB activity secondary to damage might lead to a subsequent compensatory downregulation of CREB levels.
Also, the role of adaptive cascades in physiological and pathophysiological processes is complex, and conceptually straightforward descriptions of hyperadaptive versus hypoadaptive phenotypes might not readily apply.For instance, CREB is important in both cancer progression [21] and immune function [14a] which counters cancer.It would thus not be immediately clear what result inhibiting CREB would lead to as it could lead to decreased cancer progression due to lower malignancy or increased cancer progression due to immune dysfunction.This illustrates the need for more detailed stratification.CREB and other pathways oftentimes have context-specific co-regulators that are activated differentially according to tissue and stimulus type (see a previous discussion for details [69] ).Furthermore, the effect of many molecules within the organism depends on the underlying signaling dynamics such as maximum amplitude and time-course of activation.Different activation patterns of the same molecules can have drastically different downstream effects. [57]he above points highlight the problem with overly simplistic causality models as previously explored. [89]The organism is subjected to a set of interconnected aging stimuli simultaneously right after inception.Thus, asking what would come first, damage or maladaptation, might not make much sense.Similarly, the complex regulation patterns within adaptive pathways expressing degeneracy, feedback loops, and context-dependent interactions render extraction of repeatable patterns difficult.In order to understand adaptation-maladaptation connections and how these could be uncoupled, probing the underlying dynamics of adaptation cascades will be important.

Conclusion
In conclusion, aging can be conceptualized as one failed adaptation process to a set of aging stimuli.The present work has proposed the adaptation-maladaptation dilemma as an explanation for this failure which states that aging results from the fact that the set of the body's adaptation mechanisms overlaps with the set of aging stimuli and drives progressive maladaptation.This constitutes a programming error in which the body cannot escape from the detrimental influences of its own operations, leading to inescapable progressive dysfunction over time.Adaptationmaladaptation theory posits that in order to counter maladaptation, the organism might need to reduce the output of adaptation cascades progressively.Failure to do so leads to cancer, diabetes, and autoimmunity among other disorders.Success in doing so however results in frailty, immunosenescence, and cognitive decline among other things.The adaptation-maladaptation dilemma might thus embody a logic error in organisms in that the mechanisms that counter stressors (i.e., mediating adaptation) act as stressors themselves (i.e., causing maladaptation).Consequently, stress on the system and its long-term consequences are inevitable.The combination of long-term stress leading to maladaptation and the body's attempt to counteract this maladaptation in the form of adaptation reductions might be inevitable for every organism.The organism is thus trapped in a dilemma which it cannot solve, resulting in the progressive dysfunction we call aging.Counteracting aging might be achieved by uncoupling beneficial adaptation from maladaptation, thereby allowing the organism continued absorption of stressors without introducing dysfunction.

Figure 1 .
Figure1.Biological adaptation mechanisms simultaneously implement physiological adaptation and pathological maladaptation (the "adaptationmaladaptation dilemma").The body's adaptation mechanisms, such as adaptive transcription, stimulus-dependent epigenetic remodeling, and metabolic plasticity, simultaneously implement beneficial adaptive functions (e.g., learning and memory, muscle anabolism, adaptive immunity) as well as maladaptive phenotypes (e.g., cancer, autoimmunity, type 2 diabetes).This duality delineates the adaptation-maladaptation dilemma and presents the organism with a fundamental problem: enable high activity of adaptation cascades and increase fitness but also shorten lifespan due to diseases such as cancer or decrease adaptive fitness but also decrease maladaptive disease risk and increase lifespan.

Figure 2 .
Figure 2. Aging as a two-component process with increasing maladaptation necessitating an aging program to decrease adaptative function.A), Increasing maladaptation over time leads to increased incidence of hyperadaptive age-related disorders (e.g., cancer, autoimmunity, atherosclerosis, type 2 diabetes) and constitutes the nonprogrammed component of aging.B), In order to counteract maladaptation the body might implement an aging program (e.g., through genomic methylation) which decreases adaptation mechanisms in a body-wide manner.This causes a reduction in maladaptation at the cost of also reducing many physiological adaptation phenotypes and leads to hypoadaptive symptom complexes such as dementia, sarcopenia, and immunosenescence.

Figure 3 .
Figure 3. Molecular mechanisms in the adaptation-maladaptation dilemma of aging.A).At the cellular level, inducible transcription programs involving transcription factors such as CREB, AP1, and Myc couple stimulation to cellular plasticity in both adaptive processes (e.g., learning and memory) and maladaptive ones (e.g., cancer).B), Top: Reducing CREB in C. elegans leads to a reduction in memory performance (a major hallmark of aging) but an increase in lifespan.Bottom: Reduction of the adaptive transcription factor Myc in mice leads to reduced homeostasis and accelerated aging but also to decreased cancer incidence and an increased lifespan.C), Inducible DNA damage and repair as an example of the adaptation-maladaptation dilemma.Neuronal activity induces Npas4, a neuroprotective gene important for neural plasticity, via DNA double-strand breaks (DSBs).Npas4 in turn complexes with NuA4 to repair DSBs.Similarly, BDNF induces base-excision repair genes in neurons.The induction of a beneficial adaptation mechanism is hence coupled to directed DNA damage and its repair.Hypothetically, a dysbalancing in these adaptive damage-repair loops could lead to an overtaking of maladaptive genomic damage and aging-related dysfunction.

Figure 4 .
Figure 4. Longevity interventions induce a shift in the adaptation-maladaptation balance.Longevity interventions such as exercise, environmental enrichment, and dietary restriction boost physiological adaptation capacities (e.g., learning and memory) while simultaneously decreasing maladaptation (e.g., reduced cancer incidence).Novel therapeutic approaches in pharmacology and gene therapy for aging could study and mimic this central phenotype.