Re: 70년 반감기 탄성섬유 분해 가속-- 노화관련 질환 ... 2024 nature

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📌 노화-질병 상호작용에 의한 가속화된 엘라스틴 분해 (논문 요약)

🔹 논문 제목: Accelerated Elastin Degradation by Age-Disease Interaction
🔹 저자: Naomi Shek et al. (2024)
🔹 저널: npj Aging (Nature Partner Journals)
🔹 DOI: 10.1038/s41514-024-00143-7

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📌 1. 연구 개요 및 배경

• 노화(Aging)는 심혈관질환, 만성 호흡기질환(COPD, 기관지확장증), 류마티스관절염(RA) 등과 같은 다양한 질병의 주요 위험 요인
• 노화 과정에서 조직 구조 손실 → 생리적 항상성 감소 → 환경 자극에 대한 반응 저하 → 질병 위험 증가
• **초장수 단백질(ultra-long-lived proteins, ULLP)인 엘라스틴(Elastin)**은 정상적인 노화 과정에서 자연적으로 분해되지만,
  질병과 결합될 경우 이 분해 과정이 가속화됨

🔹 연구 질문

• 엘라스틴 분해율(elastin turnover)이 단순한 노화 때문인지, 노화와 특정 질병 간의 상호작용 때문인지 분석
• COPD, 기관지확장증, AAA(복부 대동맥류), RA 등의 노화 관련 질환에서 엘라스틴 분해가 가속화되는가?

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📌 2. 연구 방법✅ 연구 대상 (Clinical Cohorts)

• 총 3,024명의 참가자 데이터를 분석
• 질병군 vs 건강한 대조군 비교

질환군샘플 수 (n)특징

COPD	1,332명	GOLD Stage II–IV COPD 환자
복부 대동맥류(AAA)	507명	평균 AAA 크기: 48mm ± 8mm
기관지확장증(Bronchiectasis)	433명	Bronchiectasis Severity Index(BSI) 측정
류마티스 관절염(RA)	111명	DAS28 점수 = 4.6 ± 1.6
대조군 (Healthy Control)	641명	정상 폐기능, 심혈관질환 없음

✅ 생물학적 지표 측정 (Biomarker Analysis)

• 혈중 Desmosine & Isodesmosine (cDES) 농도 분석
  → 이들은 엘라스틴 가교(crosslinking) 분해 산물로, 엘라스틴 분해 정도를 반영
• cDES 농도가 증가할수록 엘라스틴 분해율이 높음

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📌 3. 주요 연구 결과✅ 연령 증가에 따른 엘라스틴 분해율 (cDES 농도 증가)

• 대조군과 COPD, AAA, 기관지확장증, RA 그룹을 비교했을 때 모든 질환군에서 cDES 농도가 연령 증가에 따라 유의하게 증가
• 특히, AAA, COPD에서 cDES 증가율이 가장 가팔랐음

✅ 나이-질병 상호작용이 엘라스틴 분해율을 가속화

• COPD, 기관지확장증, AAA, RA 환자들의 엘라스틴 분해 속도가 대조군보다 훨씬 가파르게 증가
• 선형 혼합 효과 모델(Linear Mixed-Effects Model) 분석 결과:
  • 기관지확장증(Bronchiectasis): 질병군 vs 대조군 cDES 증가 속도 41%↑
  • RA(류마티스 관절염): cDES 증가 속도 66%↑
  • AAA(복부 대동맥류): cDES 증가 속도 5배↑ (p < 0.001)

🚨 즉, 단순한 노화보다 노화 + 질병 상호작용이 엘라스틴 분해를 가속화함

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📌 4. 엘라스틴 분해 가속화가 임상적 의미를 가지는 이유✅ 엘라스틴 분해와 사망률 (Mortality Risk) 연관성

• COPD, 기관지확장증, AAA 환자에서 cDES 농도가 높을수록 사망률 및 심혈관 질환(CVD) 발생률 증가
• AAA 환자에서 가장 급격한 엘라스틴 분해가 관찰됨 → AAA 파열 위험 증가 가능성
• COPD 환자 중 심혈관 질환 병력이 있는 경우, cDES 증가 속도가 더 가팔랐음

🚨 즉, 엘라스틴 분해율이 높을수록 심혈관 위험과 사망 위험이 증가

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📌 5. 가속화된 엘라스틴 분해의 생물학적 기전 (Biological Mechanisms)1️⃣ 엘라스타제(Elastase) 활성 증가

• 중성구 및 대식세포에서 분비되는 단백질 분해효소(Protease) 증가 → 엘라스틴 가수분해 촉진
• COPD, AAA 환자에서 엘라스타제 활성 증가 보고됨

2️⃣ 염증 및 면역세포 과활성

• 만성 염증 환경(예: COPD, RA, 기관지확장증) → MMP(Matrix Metalloproteinase) & 엘라스타제 증가
• 면역세포(중성구, 대식세포) 활성화 → 과도한 엘라스틴 분해 유발

3️⃣ 노화에 따른 신장 기능 저하 → 엘라스틴 분해산물 제거율 감소

• 일부 연구에서는 신장 기능 감소 시 cDES 농도 증가 보고
• 그러나 본 연구에서는 COPD에서는 신장 기능과 cDES 연관성이 발견되지 않음

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📌 6. 엘라스틴 분해를 줄이는 전략 (Potential Therapeutic Strategies)✅ 현재까지 입증된 치료법 부족

• 현재 사람에서 엘라스틴 분해를 직접 억제하는 치료법은 거의 없음
• 알파-1 항트립신 보충 요법(Alpha-1 Antitrypsin Augmentation)
  • COPD에서 순환 엘라스틴 분해산물 감소 효과 관찰
  • 그러나 치료 효과가 크지 않으며, 특정 유전적 결핍 환자(AATD)에서만 적용 가능

✅ 차세대 단백질 분해효소 억제제 (Anti-Protease Therapy)

• DPP1 억제제(Brensocatib): 기관지확장증 치료제 → 중성구 활성 감소 → 엘라스틴 분해 억제
• 노화 방지 치료(예: 칼로리 제한, 메트포르민) → 엘라스틴 보호 가능성 연구 중

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📌 7. 결론 및 임상적 시사점

1️⃣ 노화 자체도 엘라스틴 분해를 촉진하지만, 질병이 동반되면 분해 속도가 급격히 증가
2️⃣ COPD, 기관지확장증, AAA, RA 환자에서 엘라스틴 분해율이 대조군보다 현저히 높음
3️⃣ 엘라스틴 분해율 증가(cDES 증가)는 심혈관 위험 및 사망률 상승과 연관
4️⃣ 현재 효과적인 치료법이 없으며, 단백질 분해효소 억제제 및 노화 방지 치료가 대안으로 연구 중

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📌 추가 질문 가능

• 특정 질환(COPD, AAA)에서 엘라스틴 분해 기전?
• 엘라스틴 보호 및 재생을 위한 최신 연구?
• 운동, 영양이 엘라스틴 분해 억제에 미치는 영향?

1. nature  
2. npj aging  
3. brief communications  
4. article

Accelerated elastin degradation by age-disease interaction: a common feature in age-related diseases

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• Brief Communication
• Open access
• Published: 27 February 2024

Accelerated elastin degradation by age-disease interaction: a common feature in age-related diseases

• Naomi Shek, 
• Anna-Maria Choy, 
• Chim C. Lang, 
• Bruce E. Miller, 
• Ruth Tal-Singer, 
• Charlotte E. Bolton, 
• Neil C. Thomson, 
• James D. Chalmers, 
• Matt J. Bown, 
• David E. Newby, 
• Faisel Khan & 
• Jeffrey T. J. Huang 

npj Aging volume 10, Article number: 15 (2024) Cite this article

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Abstract

Aging is a major driving force for many diseases but the relationship between chronological age, the aging process and age-related diseases is not fully understood. Fragmentation and loss of ultra-long-lived elastin are key features in aging and several age-related diseases leading to increased mortality. By comparing the relationship between age and elastin turnover with healthy volunteers, we show that accelerated elastin turnover by age-disease interaction is a common feature of age-related diseases.

요약

노화는 많은 질병의 주요 원인이지만,

연대, 노화 과정, 노화 관련 질병 사이의 관계는 완전히 이해되지 않았습니다.

초장수 엘라스틴  ultra-long-lived elastin 의 분열과 손실은

노화의 주요 특징이며,

사망률을 높이는 여러 가지 노화 관련 질병의 원인입니다. '

건강한 지원자를 대상으로 연령과 엘라스틴 회전율 사이의 관계를 비교함으로써,

연령과 질병의 상호 작용에 의한 가속화된 엘라스틴 회전율이

노화 관련 질병의 공통적인 특징임을 보여줍니다.

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Introduction

Advanced age exponentially increases the risk of developing cardiovascular disease, chronic respiratory diseases including COPD and bronchiectasis, and degenerative diseases such as arthritis1. Around 100,000 people worldwide die each day due to age-related diseases2. Loss of tissue and structural integrity leading to the loss physiological integrity with age, resulting in a progressive decline of homoeostasis and reduced capacity to respond to environmental stimuli, is believed to contribute to an incremental risk and severity of these diseases3. Several intertwined biological mechanisms including shortened telomeres, epigenetics, inflammation, macromolecular damage, altered metabolism and proteostasis, and reduced stem cells and regeneration have been proposed as key mechanisms driving the loss of physiological integrity in aging and its associated diseases4. Although most studies have focused on the associations between these processes and chronological age or diseases, less attention has been drawn to their interactions where the effect of chronological age on an aging process depends on the presence of a disease.

Ultra-long lived proteins such as elastin, collagen, and eye lens crystalline have been considered as the Achilles heel of the aging proteome5 as their damages and losses are not easily repaired. Among them, elastin is unique in providing the characteristics of elasticity, resilience, and deformability of tissues such as the aorta, lung, and skin etc, and its fragmentation and degradation represents an important feature of normal aging6. Elastin is a crosslinked polymeric network of tropoelastin monomers catalysed by lysine oxidase during development. In adult tissues, elastin has an extremely low turnover rate with a half-life of ~74 years under normal conditions7 in contrast to minutes to days for most intracellular proteins8. In general, adult tissues lack the capability of regenerating functional elastic fibre9. These two unique properties imply that an increased turnover of this ultra-long-lived protein in adult tissues could result in irreversible changes to elastin-rich tissues5. Elastin breakdown products themselves are also known to possess biological activities such as chemotactism, angiogenesis, and inflammatory responses10. Monitoring the activity of elastin degradation therefore could be highly relevant to better understanding aging and aging-related diseases.

We have previously investigated the activity of elastin degradation in several age-associated diseases by eval‎uating the concentrations of circulating total desmosine and isodesmosine (termed cDES), two crosslinking molecules unique to functional elastin11,12,13,14. We found that cDES concentrations were positively associated with chronological age in patients with COPD15, bronchiectasis12,14, abdominal aortic aneurysm (AAA)13, acute myocardial infarction16, and in control participants with normal lung function and free of significant diseases15. The elevated cDES concentrations were significantly correlated with higher mortality and cardiovascular morbidity or mortality in these conditions11,12,13,14,15. Interestingly, the activity of elastin degradation was accelerated by an age-disease interaction in COPD11, supporting the concept that COPD is a disease of accelerated aging. However, whether a similar age-disease interaction also drives elastin degradation in other age-related diseases is unknown. We set out to investigate whether the age-associated elastin degradation is enhanced in AAA, bronchiectasis, rheumatoid arthritis (RA) and COPD compared to control subjects.

We performed a pooled analysis of data from multiple cohorts comprising individuals with COPD (n = 1332), AAA (n = 507), bronchiectasis (n = 433) or RA (n = 111), and a control group (n = 641). The COPD group was combined from three observational cohorts (the ECLIPSE17, Nottingham17, and Scotland cohorts18) where individuals with GOLD stage II–IV COPD were recruited. The AAA group included two cohorts (the MA3RS19 and UK Aneurysm Growth Study (UKAGS) cohorts13) where the mean AAA size was 48 mm (standard deviation=8 mm). The bronchiectasis patients were from the TAYBRIDGE cohort and had a median (IQR) Bronchiectasis Severity Index score of 6(4–10)14. RA patients meeting the 1987 American College of Rheumatology (ACR) classification criteria for RA (DAS28 score = 4.6 (1.6)) were recruited in Ninewells Hospital, Dundee. With the exception of RA and control subjects, previous history of CV disease, uncontrolled hypertension or hypercholesterolaemia and any other inflammatory conditions were not excluded in disease groups. The demographic details of each study group are shown in Supplementary Table 1. The AAA group had a higher percentage of male participants whereas the bronchiectasis and RA groups had higher percentages of females, reflecting the sex differences in the preval‎ence of those diseases and the fact that only men are screened for AAA in the UKAGS cohort20,21. As expected, the COPD and AAA groups have higher percentages of current and ex-smokers. Our previous studies have shown that sex and smoking history did not affect cDES concentrations in adults12,15. Similar to the positive associations to age observed in the COPD and control populations11, cDES concentrations correlated with age in AAA, bronchiectasis, and RA (r = 0.24–0.54, p < 0.001, Pearson/Spearman correlation, Fig. 1a–e, Supplementary Table 2).

Fig. 1: Age-dependent elastin degradation was accelerated in COPD, AAA, bronchiectasis, and rheumatoid arthritis.

a–e Scatterplots of cDES against age in control subjects without inflammatory diseases a, bronchiectasis b, RA c, COPD d, AAA e. f Predicted linear mixed model of log transformed cDES levels and age in bronchiectasis and the control group (β = 0.0048, standard error (SE) = 0.0020, p = 0.02, linear mixed effects model for age and disease interaction). Note log10(cDES) was used to ensure normality assumption for residuals and the unit is in ng/L. g Predicted linear mixed model of cDES levels and age in RA and the control group (β=0.0009, SE = 0.0003, p = 0.003, linear mixed effects model for age and disease interaction). h Predicted linear mixed model of cDES levels and age in AAA (β = 0.0030, SE = 0.0009, p < 0.001, linear mixed effects model for the age and disease interaction). i Predicted linear mixed model of cDES levels in COPD with (n = 507) or without CVDs (n = 472)( β= 0.0026, SE = 0.0013, p = 0.03, linear mixed effects model for age and disease interaction) in the ECLIPSE cohort. Solid regression lines are labelled with equations. Dashed lines represent standard deviations.

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To investigate the effect of age-disease interaction on elastin turnover, we compared the slopes of the regression lines between the four disease groups and the control population using a linear mixed-effects model incorporating subject-specific random effects and taking into account the effects of multiple visits from some individuals (i.e., in the ECLIPSE, Scotland, and MA3RS cohorts). We found that the slope of age to elastin turnover regression in bronchiectasis was greater compared to healthy control subjects (6.27 vs 4.45 pg L-1 (log10) per year, p = 0.02, linear mixed effects model for the interaction, Fig. 1f). A similar effect of age-disease interaction was found in RA (5.75 vs 3.46 ng L-1 per year, p = 0.003, linear mixed effects model, Fig. 1g). In the AAA group the predicted regression slopes is ~5 times greater (16 ng L-1 per year) when compared to the control population (3.12 ng L-1 per year; p < 0.001; linear mixed effects model, Fig. 1h). The difference remained if those less than 60 years old (defined by the lower limit of 95% interval of the AAA group) in the control group were excluded (p = 0.007, linear mixed effects model). Together with the previous observation in COPD11, these results strongly suggest that RA, AAA, bronchiectasis, and COPD are diseases of accelerated elastin turnover driven by an age-disease interaction where the differences between the disease groups and control becomes greater as age increases.

Increased cDES concentrations have implications for mortality in COPD15, bronchiectasis14, and AAA13. Notably, the association between cDES concentrations and cardiovascular diseases was particularly strong among these diseases, probably explained by the abundant presence of elastin in the vascular system. Indeed, a significant interaction (greater slope) was also observed in COPD patients with cardiovascular diseases (defined as self-reported history of hypertension, myocardial infarction, angina, and stroke) compared to COPD participants without in the ECLIPSE cohort (8.69 ng vs 5.48 ng L-1 per year, p = 0.03, linear mixed effects model, Fig. 1i). The notion is also supported by the fact that among the four diseases studied, AAA showed the greatest slope, possibly reflecting the severe nature of elastin degradation22 and the high cardiovascular risk known for this group of patients23. Furthermore, cDES concentrations were significantly associated with pulse wave velocity (a measure of arterial stiffness) in patients with COPD15 and acute myocardial infarction16 further strengthening its clinical relevance to the cardiovascular system with elastin breakdown mirroring arterial stiffness. These data may provide a potential explanation as to why cardiovascular morbidities and mortality are higher in COPD, RA, and bronchiectasis.

It is unclear how this observed age-disease interactions occur across these diseases caused by different aetiologies. It is plausible that old age increases the expansion of blood cells with somatic mutations (or clonal haematopoiesis)24, leading to over-activation of immune cells such as neutrophils and macrophages to disease-causing pathogens or reactants25, subsequently releasing more proteolytic enzymes to the circulation that digest elastin in the vasculature. Another possibility previously suggested by skin aging studies is that intrinsic aging processes could make elastin more vulnerable over time to elastases stimulated by an extrinsic stimulus or a disease (6). In addition, age associated decline of renal function might also influence the elimination of cDES and cDES containing peptides from the circulation leading to higher cDES concentrations, although our current evidence did not show consistency. In our two previous studies where renal function data are available, we found an association between renal function and cDES concentrations in acute myocardial infarction16 but not in COPD15. The reason for this discrepancy is unclear but it is possible that the disease population or patient conditions (e.g., acute vs stable condition) could affect the relationship.

Few proven interventions are available that prevent or minimise elastin degradation in humans. To date, alpha-1 antitrypsin augmentation is the only treatment showing the ability of reducing circulating desmosine levels in a randomised trial although the magnitude of treatment effect was small26 and it is currently only relevant to alpha-1 antitrypsin deficiency, a rare genetic condition that is associated with emphysema. Next generation systematic anti-proteinase therapy such as DPP1 inhibitors may offer promise especially for bronchiectasis27. It would be of great interest to test whether anti-aging therapies such as calorie restriction and caloric restriction mimetics (e.g., metformin) could impact elastin degradation in age-related diseases in human. A recent animal study showing that calorie restriction was able to reduce arterial aging by reducing proinflammation associated elastin degradation supports this concept28.

We acknowledge several limitations in this study. First, we were not able to estimate the contribution of renal function to the observed age-disease interaction due to the lack of data availability. Second, the comorbidity data were not always available and therefore the influence of the comorbidity cannot be always excluded. Third, we did not include the acute myocardial infarction study16 in the current study as the data were not available.

In summary, we conclude that accelerated elastin degradation by age-disease interaction is a common feature in age-related diseases.

Methods

Clinical cohorts

Multiple cohorts comprising individuals with COPD, AAA, bronchiectasis or RA, and a control group were included in this study. The COPD group was combined from three observational cohorts (the ECLIPSE17(ClinicalTrials.gov Identifier: NCT00292552), Nottingham17, and Scotland cohorts18). The AAA group included two cohorts (the MA3RS19(ClinicalTrials.gov Identifier: NCT02229006) and UKAGS cohorts13). The bronchiectasis patients were from the TAYBRIDGE cohort14. RA patients meeting the 1987 ACR classification criteria for RA were recruited in Ninewells Hospital, Dundee. Ethic approvals and informed consent have been obtained and the details can be found in previous reports13,14,17,18,19.

cDES quantification

cDES concentrations were measured using the same validated isotope dilution LC-MS/MS method29 in the same laboratory.

Statistical analysis

Correlation analysis and linear mixed-effects modelling were carried out using SPSS (version 25, IBM). For linear mixed modelling, the fixed effects included age, disease groups (e.g., COPD vs control), as well as the interaction between age and disease groups. Effects from repeated measurements were controlled for. The random effects included intercept and/or age using two covariance structures (variance components or unstructured). The Akaike information criterion was utilised to select the best valid model that yielded the lowest AIC. The normality of residuals was checked by Q-Q plots and the homogeneity of variance by scatter plots of residuals and predicted values. A p value of 0.05 was considered significant.

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Data availability

The clinical data for the ECLIPSE cohort is available at dbGaP (Study Accession: phs001252.v1.p1). Other data are available from the corresponding author on reasonable request.

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