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<p>Aging is increasingly understood not as the passive accumulation of molecular damage, but as the cumulative cost of unresolved physiological adaptation under bioenergetic constraint. This review introduces <i>Exposure-Related Malnutrition (ERM)</i> as a mechanistically grounded and clinically actionable phenotype of early maladaptation. ERM arises from sustained metabolic strain during chronic stress exposure and manifests not through overt weight loss or nutrient deficiency, but through subtle, multisystem declines in physical, cognitive, and regenerative capacity. These include fatigue, impaired recovery, cognitive slowing, immune dysregulation, chronic pain, anabolic resistance, and reproductive decline—features often missed by classical malnutrition criteria. We propose a unifying framework—<i>Respond → Adapt → Resolve</i>—to model the trajectory of stress response and resolution, emphasizing the critical role of bioenergetic availability in shaping divergent outcomes. When metabolic substrates are insufficient, resolution fails and the system defaults to a trade-off state, prioritizing immediate survival over long-term maintenance. ERM represents this inflection point: a reversible, energy-constrained condition that precedes frailty and chronic disease. We review interconnected mechanisms—including neuroendocrine activation, immune reprogramming, skeletal muscle catabolism, translational suppression, and mitochondrial distress—that create a self-perpetuating loop of maladaptive adaptation. We map ERM onto key hallmarks of aging, propose a multidimensional staging model, and outline clinical strategies to detect and reverse ERM using dynamic biomarkers, functional assessments, and circadian-aligned lifestyle interventions. By reframing aging as a failure of adaptive resolution, this framework offers a novel lens to extend healthspan—via early detection of metabolic compromise and restoration of resilience before functional decline becomes irreversible.</p> Graphical abstract <p>This model illustrates the trajectory of stress adaptation and resolution, highlighting how divergent outcomes—hormesis, homeostasis, or maladaptation—are shaped by energy and substrate availability. Exposure-Related Malnutrition (ERM) represents a subclinical, reversible state of unresolved adaptation under chronic bioenergetic strain. As allostatic load increases and nutrient support declines, ERM may progress toward maladaptation and age-related disease. Early recognition and restoration of resolution capacity may preserve resilience and delay dysfunction.</p> <p></p>

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From adaptation to exhaustion: defining exposure-related malnutrition as a bioenergetic phenotype of aging

  • 期刊论文

  • 发表日期：

    2025年8月13日

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  • Torsak Tippairote,
  • Pruettithada Hoonkaew,
  • Aunchisa Suksawang,
  • Prayfan Tippairote

摘要

Aging is increasingly understood not as the passive accumulation of molecular damage, but as the cumulative cost of unresolved physiological adaptation under bioenergetic constraint. This review introduces Exposure-Related Malnutrition (ERM) as a mechanistically grounded and clinically actionable phenotype of early maladaptation. ERM arises from sustained metabolic strain during chronic stress exposure and manifests not through overt weight loss or nutrient deficiency, but through subtle, multisystem declines in physical, cognitive, and regenerative capacity. These include fatigue, impaired recovery, cognitive slowing, immune dysregulation, chronic pain, anabolic resistance, and reproductive decline—features often missed by classical malnutrition criteria. We propose a unifying framework—Respond → Adapt → Resolve—to model the trajectory of stress response and resolution, emphasizing the critical role of bioenergetic availability in shaping divergent outcomes. When metabolic substrates are insufficient, resolution fails and the system defaults to a trade-off state, prioritizing immediate survival over long-term maintenance. ERM represents this inflection point: a reversible, energy-constrained condition that precedes frailty and chronic disease. We review interconnected mechanisms—including neuroendocrine activation, immune reprogramming, skeletal muscle catabolism, translational suppression, and mitochondrial distress—that create a self-perpetuating loop of maladaptive adaptation. We map ERM onto key hallmarks of aging, propose a multidimensional staging model, and outline clinical strategies to detect and reverse ERM using dynamic biomarkers, functional assessments, and circadian-aligned lifestyle interventions. By reframing aging as a failure of adaptive resolution, this framework offers a novel lens to extend healthspan—via early detection of metabolic compromise and restoration of resilience before functional decline becomes irreversible.

Graphical abstract

This model illustrates the trajectory of stress adaptation and resolution, highlighting how divergent outcomes—hormesis, homeostasis, or maladaptation—are shaped by energy and substrate availability. Exposure-Related Malnutrition (ERM) represents a subclinical, reversible state of unresolved adaptation under chronic bioenergetic strain. As allostatic load increases and nutrient support declines, ERM may progress toward maladaptation and age-related disease. Early recognition and restoration of resolution capacity may preserve resilience and delay dysfunction.