나이가 들수록 몸 곳곳에서 다양한 질병이 동시에 나타나는 경향이 있다. 심장병, 당뇨, 치매, 암 — 이 질환들이 서로 무관해 보이지만 공통된 뿌리를 가질 수 있다는 연구가 주목받고 있다. 그 핵심 연결 고리로 S100A8/A9 단백질이 지목됐다.
*Ageing Research Reviews*에 발표된 이 종합 리뷰는 S100A8/A9의 구조, 기능, 그리고 다양한 조직과 질병에서의 역할을 체계적으로 정리했다. S100A8과 S100A9는 각각 칼리프로텍틴(calprotectin)의 구성 단백질로, 염증 반응이 일어날 때 백혈구에서 대량 분비된다.
이 단백질은 세포 밖에서는 백혈구 유착을 촉진하고 면역 억제 세포(MDSC)를 집합시킨다. 세포 안에서는 NLRP3 인플라마솜을 활성화하고, 아라키돈산 대사를 조절하며, 자가포식과 세포 사멸에도 관여한다. 이를 통해 노화 → 염증 → 더 심한 노화로 이어지는 양성 피드백 루프가 형성된다.
다계통 분석 결과, S100A8/A9 발현 증가는 종양에서는 면역 억제와 항암 치료 저항성을 유도하고, 신경계에서는 호중구 세포외 덫(NET)과 페로토시스를 통해 신경 손상을 촉진했다. 심혈관계에서는 내피 노화와 동맥경화 플라크 불안정성을 가속화하며, 대사 측면에서는 지방 조직 기능 장애와 인슐린 저항성을 유발한다. 근육에서는 근감소와 노쇠(frailty)를 촉진하는 역할도 한다.
S100A8/A9는 혈청 수치로 측정 가능하며, 여러 질환의 활성도, 치료 저항성, 불량한 예후를 반영하는 바이오마커로서의 활용 가능성도 주목된다. 이는 암, 자가면역 질환, 심혈관 질환의 위험 계층화에 실용적으로 사용될 수 있음을 의미한다.
치료 전략 측면에서, S100A8/A9-TLR4 축을 표적으로 하거나 S100A9를 중화하는 전략이 동물 모델에서 염증 감소 및 질병 진행 지연 효과를 보였다. 단, 현재까지 인체 임상 시험 데이터는 제한적이며 리뷰 논문의 특성상 직접적인 인과관계 증명에 한계가 있다.
일상에서 만성 염증을 줄이는 생활 습관 — 규칙적인 운동, 가공식품 및 설탕 제한, 충분한 수면, 스트레스 관리 — 이 S100A8/A9 과활성화를 억제하는 데 도움이 될 수 있다. 올리브 오일, 감귤류 등 지중해 식단 성분도 이 단백질과 관련된 염증 경로를 조절하는 것으로 알려져 있다.
📖 *S100A8/A9 as a central hub in inflammaging: Cross-system mechanisms (종합 리뷰)* |
논문 원문
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Heart disease, Alzheimer's, cancer, diabetes, muscle wasting — these conditions look quite different on the surface, but growing evidence suggests they may share a common molecular accelerator. That accelerator is a small protein complex called S100A8/A9, and understanding its role in aging could open new doors for extending healthy life.
A sweeping review published in *Ageing Research Reviews* positions S100A8/A9 as a central hub in what researchers call "inflammaging" — the low-grade, chronic inflammation that smolders in aging bodies and quietly fuels disease across virtually every organ system.
What Is S100A8/A9?
S100A8 and S100A9 are calcium-binding proteins predominantly expressed in white blood cells (neutrophils and monocytes). Together they form a complex called calprotectin, which is released in large quantities during inflammation. Most clinicians recognize elevated S100A8/A9 as an inflammation marker in conditions like sepsis and inflammatory bowel disease — but its role in the aging process is only now being fully mapped.
A Self-Reinforcing Loop Between Aging and Inflammation
What makes S100A8/A9 particularly dangerous in aging is that it doesn't just respond to inflammation — it actively perpetuates it. Outside cells, the complex promotes white blood cell adhesion to vessel walls and drives the accumulation of myeloid-derived suppressor cells (MDSCs), which blunt the immune system's ability to clear damaged cells and pathogens.
Inside cells, S100A8/A9 activates the NLRP3 inflammasome — a molecular danger-sensing complex that triggers the release of inflammatory cytokines like IL-1β and IL-18. It also regulates arachidonic acid metabolism, suppresses cellular "housekeeping" via autophagy, and can push cells toward apoptosis (programmed death). The net effect is a positive feedback loop: aging raises S100A8/A9 levels, which intensifies inflammation, which accelerates cellular aging.
Disease Across Every System
The review's authors systematically traced S100A8/A9's fingerprints across the body:
- Cancer: The protein fosters an immunosuppressive tumor microenvironment and promotes resistance to chemotherapy, making tumors harder to treat.
- Brain: Elevated S100A8/A9 drives neuroinflammation through neutrophil extracellular traps and ferroptosis — an iron-dependent form of cell death that causes neuronal damage in Alzheimer's and related diseases.
- Heart and vessels: The complex accelerates endothelial cell aging and destabilizes atherosclerotic plaques, raising the risk of heart attack and stroke.
- Metabolism: S100A8/A9 contributes to adipose tissue dysfunction and insulin resistance, linking it to type 2 diabetes and metabolic syndrome.
- Muscle: In skeletal muscle, it promotes atrophy and contributes to frailty — the progressive weakness and vulnerability that defines late-stage aging.
A Biomarker and a Target
Beyond its mechanistic roles, S100A8/A9 shows practical value as a blood-based biomarker. Its serum levels correlate with disease activity, treatment resistance, and poor prognosis across multiple conditions, suggesting it could help stratify risk in cancer, autoimmune disease, and cardiovascular disease.
On the therapeutic side, strategies targeting the S100A8/A9-TLR4 (Toll-like receptor 4) signaling axis, or directly neutralizing S100A9, have shown promising results in animal models — reducing tissue inflammation and slowing disease progression. Human clinical trials remain limited, and this review does not establish causality for any specific disease outcome.
What You Can Do
While pharmaceutical targeting of S100A8/A9 is still in early stages, lifestyle interventions that broadly reduce chronic inflammation can help. Regular moderate-intensity exercise, a diet rich in anti-inflammatory foods (olive oil, fatty fish, citrus, leafy greens), adequate sleep, and stress management are all associated with lower inflammatory tone.
Notably, several natural compounds found in Mediterranean diet foods — including polyphenols from olives and flavonoids from citrus — have been shown to modulate the same inflammatory pathways where S100A8/A9 operates, providing a plausible dietary link to reduced inflammaging.
📖 *S100A8/A9 as a central hub in inflammaging: Cross-system mechanisms (Review)* |
Source
※ This article is based on a published medical study. Individual health circumstances vary — consult your physician before making any changes to your care.
