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<p>Rheumatoid arthritis (RA) disproportionately affects adults over 50 years of age, highlighting how age-related immune remodelling undermines tolerance and promotes autoreactivity. In later adulthood, immune cells progressively lose metabolic resilience because of impaired nutrient sensing, reduced metabolic flexibility and disrupted anabolic–catabolic balance. In RA, these vulnerabilities are compounded by mitochondrial insufficiency across innate and adaptive immune lineages, creating a state of nutrient deprivation characterized by NAD⁺ and ATP scarcity and diversion of carbon away from oxidative phosphorylation. Mechanistic studies identify this bioenergetic fragility as a core defect that limits cellular longevity and promotes inflammatory, non-apoptotic death pathways, including pyroptosis and PANoptosis. The hypoxic, nutrient-restricted synovial environment adds pressure that exceeds the diminished metabolic adaptability of aged immune cells. In RA T cells, accelerated mitochondrial injury initiates maladaptive stress responses, disrupts mitochondria–lysosome–endoplasmic reticulum communication and induces gasdermin D-dependent pore formation and inflammatory lysis. Synovial MerTK⁺ reparative macrophages undergo a parallel metabolic crisis, whereby autocrine C1q sensing activates mitochondrial SARM1, causing NAD⁺ degradation, ATP depletion and PANoptotic cell death. Together, these findings position ageing-associated metabolic exhaustion and organelle disintegration as unifying mechanisms that convert immune cells into tissue-damaging effectors and explain the heightened susceptibility to RA in older adults.</p>

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Metabolic exhaustion and immune ageing in rheumatoid arthritis

  • 期刊论文

  • 发表日期：

    2026年8月3日

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  • Cornelia M. Weyand,
  • Jörg J. Goronzy

摘要

Rheumatoid arthritis (RA) disproportionately affects adults over 50 years of age, highlighting how age-related immune remodelling undermines tolerance and promotes autoreactivity. In later adulthood, immune cells progressively lose metabolic resilience because of impaired nutrient sensing, reduced metabolic flexibility and disrupted anabolic–catabolic balance. In RA, these vulnerabilities are compounded by mitochondrial insufficiency across innate and adaptive immune lineages, creating a state of nutrient deprivation characterized by NAD⁺ and ATP scarcity and diversion of carbon away from oxidative phosphorylation. Mechanistic studies identify this bioenergetic fragility as a core defect that limits cellular longevity and promotes inflammatory, non-apoptotic death pathways, including pyroptosis and PANoptosis. The hypoxic, nutrient-restricted synovial environment adds pressure that exceeds the diminished metabolic adaptability of aged immune cells. In RA T cells, accelerated mitochondrial injury initiates maladaptive stress responses, disrupts mitochondria–lysosome–endoplasmic reticulum communication and induces gasdermin D-dependent pore formation and inflammatory lysis. Synovial MerTK⁺ reparative macrophages undergo a parallel metabolic crisis, whereby autocrine C1q sensing activates mitochondrial SARM1, causing NAD⁺ degradation, ATP depletion and PANoptotic cell death. Together, these findings position ageing-associated metabolic exhaustion and organelle disintegration as unifying mechanisms that convert immune cells into tissue-damaging effectors and explain the heightened susceptibility to RA in older adults.