Re: 항노화 탐구 염증성 노화, 면역세포 노화.. 2023 nature

[문형철]

https://www.nature.com/articles/s41392-023-01502-8

핵심 요약 (Abstract)

노화는

전신 만성 염증 (inflammaging) 이 특징이며,

이는 세포 노화(senescence), 면역 노화(immunosenescence), 장기 기능 저하, 노화 관련 질환과 함께 나타납니다.

노화된 세포가 분비하는

SASP (Senescence-Associated Secretory Phenotype) 가

만성 염증을 촉진하고,

정상 세포까지 노화시키는 악순환을 만듭니다.

반대로

만성 염증은

면역세포를 노화시켜 노화 세포와 염증 물질을 제거하지 못하게 하고,

이 악순환이 계속됩니다.

골수, 간, 폐 등 장기에서

염증이 지속되면 장기 손상과 질환이 발생합니다.

따라서

염증 제거 = 항노화 전략의 핵심으로 보고 있습니다.

논문은

분자·세포·장기·질환 수준에서 inflammaging을 체계적으로 정리하고,

노화 모델, 최신 단일세포 기술, 항노화 전략을 리뷰합니다.

주요 내용 구조

1. 서론: Inflammaging 개념 소개 (저급 만성 염증 + 면역 노화). 칼로리 제한 연구부터 시작해, 여성 vs 남성, 백세인 연구 등을 인용.
2. 세포 수준:
   • 조혈모세포(HSC): 염증으로 인해 골수 편향(myeloid bias), 자가재생 능력 저하, ROS 증가.
   • 호중구, 단핵구/대식세포, T세포, B세포 등 면역세포의 기능 저하와 SASP 분비.
   • 
3. 분자 수준: NF-κB, cGAS-STING, NLRP3 인플라마좀, SASP 관련 신호 경로, 다양한 세포사 (pyroptosis, necroptosis, ferroptosis, NETosis, PANoptosis)와 염증 연관.
   
   
4. 장기 수준: 골수, thymus, 간, 폐, 심장, 뇌, 근육 등에서 염증이 어떻게 장기 노화를 가속화하는지.
5. 노화 모델: In vitro (복제노화, oncogene-induced 등), in vivo (동물 모델, premature aging 모델, naked mole-rat 등 장수 동물).
6. 최신 기술: 단일세포 시퀀싱 등으로 inflammaging 연구.
7. 개입 치료 (Intervention therapies):
   • Senolytic 약물 (노화세포 선택적 제거)
   • SASP 억제
   • 항염증 약물, 칼로리 제한, 운동, metformin, rapamycin 등
   • 최신 신호 경로 타겟 (cGAS-STING 등)

왜 중요한가?

노화를

“단순한 시간 경과”가 아니라 염증 중심의 생물학적 과정으로 재정의하고,

구체적인 분자 메커니즘과 치료 타겟을 제시합니다.

특히 염증-노화 악순환을 깨는 전략이

미래 항노화 치료의 핵심이 될 수 있다고 강조

1. nature  
2. signal transduction and targeted therapy  
3. review articles  
4. article

Inflammation and aging: signaling pathways and intervention therapies

Download PDF

• Review Article
• Open access
• Published: 08 June 2023

Inflammation and aging: signaling pathways and intervention therapies

• Xia Li, 
• Chentao Li, 
• Wanying Zhang, 
• Yanan Wang, 
• Pengxu Qian & 
• He Huang 

Signal Transduction and Targeted Therapy volume 8, Article number: 239 (2023) Cite this article

•  
•  
•  

Abstract

Aging is characterized by systemic chronic inflammation, which is accompanied by cellular senescence, immunosenescence, organ dysfunction, and age-related diseases. Given the multidimensional complexity of aging, there is an urgent need for a systematic organization of inflammaging through dimensionality reduction. Factors secreted by senescent cells, known as the senescence-associated secretory phenotype (SASP), promote chronic inflammation and can induce senescence in normal cells. At the same time, chronic inflammation accelerates the senescence of immune cells, resulting in weakened immune function and an inability to clear senescent cells and inflammatory factors, which creates a vicious cycle of inflammation and senescence. Persistently elevated inflammation levels in organs such as the bone marrow, liver, and lungs cannot be eliminated in time, leading to organ damage and aging-related diseases. Therefore, inflammation has been recognized as an endogenous factor in aging, and the elimination of inflammation could be a potential strategy for anti-aging. Here we discuss inflammaging at the molecular, cellular, organ, and disease levels, and review current aging models, the implications of cutting-edge single cell technologies, as well as anti-aging strategies. Since preventing and alleviating aging-related diseases and improving the overall quality of life are the ultimate goals of aging research, our review highlights the critical features and potential mechanisms of inflammation and aging, along with the latest developments and future directions in aging research, providing a theoretical foundation for novel and practical anti-aging strategies.

노화는 

전신성 만성 염증으로 특징지어지며, 

이는 세포 노화, 면역 노화, 장기 기능 장애, 및 연령 관련 질환과 동반됩니다. 

노화의 다차원적 복잡성 고려 시, 차원 축소를 통한 

염증 노화(inflammaging)의 체계적 조직화가 시급히 필요합니다. 

노화 세포에서 분비되는 인자들로 구성된 노화 관련 분비 형질(SASP)은 

만성 염증을 촉진하며 정상 세포의 노화를 유도할 수 있습니다. 

동시에 만성 염증은 

면역 세포의 노화를 가속화하여 면역 기능 약화와 노화 세포 및 염증 인자의 제거 실패를 초래하며, 

이는 염증과 노화의 악순환을 형성합니다. 

골수, 간, 폐 등 장기에서 지속적으로 상승한 염증 수준은 

적시에 제거되지 않아 장기 손상과 노화 관련 질환을 유발합니다. 

따라서 

염증은 노화의 내인성 요인으로 인정되었으며, 

염증 제거는 노화 방지 전략의 잠재적 접근법으로 제시되고 있습니다. 

본 연구에서는 분자, 세포, 장기, 질환 수준에서의 염증과 노화를 논의하며, 현재의 노화 모델, 최신 단일 세포 기술의 함의, 그리고 노화 방지 전략을 검토합니다. 노화 관련 질환의 예방 및 완화, 전반적인 삶의 질 개선이 노화 연구의 궁극적인 목표인 만큼, 본 리뷰는 염증과 노화의 핵심 특징과 잠재적 메커니즘을 강조하며, 노화 연구의 최신 동향과 미래 방향을 제시하여 새로운 실용적 노화 방지 전략의 이론적 기반을 제공합니다.

Similar content being viewed by others

TXNRD1 drives the innate immune response in senescent cells with implications for age-associated inflammation

Article 24 January 2024

Strategies for targeting senescent cells in human disease

Article 07 October 2021

Senescence as a therapeutic target in cancer and age-related diseases

Article 15 November 2024

Introduction

Aging is a common, complex, and natural phenomenon. Aging research began in 1939 with the observation that restricting calorie intake could prolong life both in mice and rats.1 To further explain aging from the perspective of harmful inflammation and weakened immunity, inflammaging was introduced as an evolutionary perspective on immunosenescence, referring to the phenomenon of low-grade, chronic damage resulting from increased inflammation levels within the body.2 Later, inflammaging has been considered a hallmark of aging.3 Meanwhile, it is worth mentioning that can also damage the immune system, leading to immunosenescence during aging. For example, studies have shown that women living longer than men,4 in which older men showed higher activity of inflammation-related modules, with a more dramatic decrease in the ratio of naive T and B cells compared to older women.4,5 In addition, centenarians have been found to possess stronger anti-inflammatory abilities, suggesting that inflammation and immunity may a significant impact on the process of aging.6,7

Considering the complexity of aging, multi-modal and multi-perspective studies are important. The process and accumulation of cellular senescence contribute significantly to the development of organ damage and diseases in organisms. Organ and organismal aging are often accompanied by the generation of inflammatory responses, and inflammation-associated molecular patterns promote cellular senescence, which in turn can lead to further inflammation, creating a vicious cycle (Fig. 1). In this review, we have discussed the concept of inflammaging across spatial and temporal scales, and complex factors leading to aging. We have also reviewed aging models, cutting-edge technologies in aging studies, and anti-aging strategies. Considering that preventing and alleviating the aging diseases and improving quality of life are the ultimate goals of aging research, our review shows current progress and directions in aging studies and provides a theoretical basis for new and feasible anti-aging strategies.

서론

노화는 일반적이며 복잡하고 자연스러운 현상입니다.

노화 연구는

1939년 칼로리 섭취를 제한하면 쥐와 쥐에서 수명을 연장할 수 있다는 관찰로부터 시작되었습니다. 1

노화를 유해한 염증과 약화된 면역 체계의 관점에서 설명하기 위해,

염증성 노화(inflammaging)가

면역 노화(immunosenescence)의 진화적 관점으로 도입되었습니다.

이는 신체 내 염증 수준 증가로 인한 저등급의 만성적 손상을 의미합니다.2

이후 염증성 노화는 노화의 특징으로 간주되었습니다.3

한편,

노화 과정에서 면역 체계를 손상시켜

면역 노화를 유발할 수 있다는 점도 주목할 만합니다.

예를 들어,

남성보다 오래 사는 여성에 대한 연구에서,4

노인 남성은 염증 관련 모듈의 활동이 더 높았으며,

노인 여성에 비해 순수 T 세포와 B 세포의 비율이 더 급격히 감소했습니다.4,5

또한,

100세 이상 장수자들은

더 강한 항염증 능력을 갖추고 있는 것으로 밝혀져,

염증과 면역이 노화 과정에 중요한 영향을 미칠 수 있음을 시사합니다.6,7

노화의 복잡성을 고려할 때 다모달 및 다각도 연구가 중요합니다.

세포 노화의 과정과 축적은

유기체의 장기 손상과 질병 발생에 크게 기여합니다.

장기 및 유기체 노화는

종종 염증 반응의 발생과 동반되며,

염증 관련 분자 패턴은 세포 노화를 촉진하며,

이는 다시 염증을 유발해 악순환을 형성합니다(그림 1).

이 리뷰에서는 공간적 및 시간적 규모를 아우르는

염증성 노화(inflammaging)의 개념과 노화에 이르는 복잡한 요인들을 논의했습니다.

또한 노화 모델, 노화 연구 분야의 최신 기술, 항노화 전략을 검토했습니다.

노화 질환의 예방 및 완화, 삶의 질 개선이 노화 연구의 궁극적인 목표임을 고려할 때,

본 리뷰는 노화 연구의 현재 진전과 방향을 제시하며 새로운 실용적인 항노화 전략의 이론적 기반을 제공합니다.

Fig. 1

Inflammaging at the molecular, cellular, and organ levels. During the aging process, almost all cells in the body undergo senescence, a state characterized by a dysfunctional state and senescence-associated secretory phenotype (SASP). While immune cells play a crucial role in recognizing and eliminating these senescent cells, they are also affected by SASP, leading to a phenomenon called immunosenescence. Immunosenescence can impair the immunity to respond to infections and diseases, making the organism more vulnerable to illnesses. Moreover, the accumulation of senescent cells can trigger inflammation in organs, leading to organ damage and an increased risk of age-related diseases. This process is exacerbated by positive feedback loops that drive the accumulation of inflammation and organ damage, leading to further inflammation and an even higher risk of aging-related diseases

분자적, 세포적, 장기적 수준에서의 염증성 노화. 

노화 과정 중 신체 내 거의 모든 세포는 

기능 장애 상태와 노화 관련 분비 형질(SASP)을 특징으로 하는 노화 상태를 겪습니다. 

면역 세포는 

이러한 노화 세포를 인식하고 제거하는 데 중요한 역할을 하지만, 

SASP의 영향을 받아 면역 노화 현상이 발생합니다. 

면역 노화는 

감염 및 질병에 대한 면역 반응을 저하시켜 

유기체가 질병에 더 취약해지게 합니다. 

또한 

노화 세포의 축적은 

장기에 염증을 유발해 장기 손상을 초래하고 노화 관련 질환의 위험을 증가시킵니다. 

이 과정은 

염증과 장기 손상을 촉진하는 긍정적 피드백 루프에 의해 악화되어 

더 심각한 염증과 노화 관련 질환의 위험이 더욱 높아집니다.

Full size image

Inflammaging at the cellular level

As the basic unit of the body, cellular senescence and the accompanying low-energy effects drive organismal aging. Recent studies have systematically summarized the biomarkers of cellular aging.8,9 Immunocytes, as key regulators of aging cells, have always been a focus of research due to their dysfunctional changes during aging.10,11 As early as 1969, Walford proposed “the immunologic theory of aging”,12 which further developed into the concept of immunosenescence, which is mainly manifested by a decrease of the body’s immune response to endogenous and exogenous antigens, leading to a decrease of the individual’s anti-tumor capacity and the ability to clear senescent cells (Fig. 1).13 Immunosenescence is a multifactorial cascade of events with different types of immune cells exhibiting different sensitivities.14,15 However, due to the inherent complexity of the mechanisms of immunosenescence, it is imperative to conduct research on immune cellular changes in multi-modal and systematic ways.

세포 수준에서의 염증성 노화

신체의 기본 단위인 세포 노화와 동반되는 저에너지 효과는 유기체의 노화를 촉진합니다. 최근 연구들은 세포 노화의 생물학적 지표들을 체계적으로 정리했습니다.8,9

면역세포는 노화 세포의 주요 조절자로서, 노화 과정에서 기능 장애 변화를 보이기 때문에 항상 연구의 초점이 되어 왔습니다. 10,11

1969년 Walford는

“면역학적 노화 이론”을 제안했으며,12

이는 면역 노화(immunosenescence) 개념으로 발전했습니다.

이는 주로 내인성 및 외인성 항원에 대한 신체 면역 반응의 감소로 나타납니다.

이는

개인의 항종양 능력과 노화 세포 제거 능력의 감소로 이어집니다(그림 1). 13

면역 노화는

다양한 면역 세포가 서로 다른 민감성을 보이는 다인자적 연쇄 반응입니다.14,15

그러나

면역 노화의 메커니즘이 본질적으로 복잡하기 때문에,

면역 세포의 변화를 다모달적이고 체계적인 방식으로 연구하는 것이 필수적입니다.

Hematopoietic stem cells (HSCs)

Senescence of HSCs is the basis of immunosenescence. Senescent HSC differentiate into various types of dysfunctional immune cells, driving immunosenescence.16 Inflammation drives impaired self-renewal activity and accelerates aging of HSCs. Exposure to inflammatory stimuli during the early to mid-life stages in mice can lead to the eventual development of peripheral blood hemocytopenia, bone marrow (BM) cytopenia, and BM adipocyte accumulation, features that together constitute typical features of hematopoiesis in the elderly.17 The primary features of senescent HSC are characterized by changes in their self-renewal, differentiation bias, and energy metabolism (Fig. 2).

혈액 생성 줄기세포 (HSCs)

HSCs의 노화는

면역 노화의 기반이 됩니다.

노화된 HSCs는

다양한 기능 장애를 가진 면역 세포로 분화되어

면역 노화를 촉진합니다.16

염증은

HSCs의 자기 재생 활동을 손상시키고 노화를 가속화합니다.

쥐의 초기부터 중년기 단계에서 염증 자극에 노출되면 결국

말초 혈액 혈구 감소증,

골수(BM) 혈구 감소증,

BM 지방세포 축적 등이 발생하며,

이러한 특징들은 노인에서 혈액 생성(hematopoiesis)의 전형적인 특징을 구성합니다.17

peripheral blood hemocytopenia,

bone marrow (BM) cytopenia, and

BM adipocyte accumulation

노화된 HSC의 주요 특징은

자기 재생 변화, 분화 편향, 에너지 대사 변화로 특징지어집니다(그림 2).

Fig. 2

Characterization of HSC differentiation into immune cells during aging. Inflammation in senescent bone marrow impairs the function of HSCs. HSCs differentiate into various immune cells, and their senescence leads to changes in the number and functions of immune cells. Common features of immune cell senescence include a decline in performing immune functions and an increase in the release of inflammatory factors

노화 과정에서 HSC의 면역 세포 분화 특성 분석. 

노화된 골수에서의 염증은 HSC의 기능을 저해합니다. HSC는 다양한 면역 세포로 분화되며, 그 노화는 면역 세포의 수와 기능에 변화를 초래합니다. 면역 세포 노화의 공통된 특징에는 면역 기능 수행 능력의 감소와 염증 인자 분비 증가가 포함됩니다.

Full size image

The increased myeloid/megakaryocytic differentiation bias is a major feature of senescent HSC.18 Numerous pro-inflammatory cytokines and growth factors, including granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1, IL-3, IL-6, TNF-α, IFNs, and Flt3 ligands, have been found to promote the differentiation of hematopoietic stem/progenitor cells (HSPCs) towards myeloid cells over lymphoid cells, leading to imbalanced myelopoiesis and lymphopoiesis.19,20,21 For example, plasma cells that have accumulated in the bone marrow of aged mice can create a feedback loop of pro-inflammatory cytokines, such as IL-1 and TNF-α, which promote HSC myeloid differentiation bias.22 According to recent studies, bone marrow cells in senescent mice secrete more IL-1α/β,23 while damaged endosteum produces IL-1β to drive inflammation in the central bone marrow in trans to impede hematopoietic regeneration.24 When faced with in vivo stimulation by lipopolysaccharide (mimicking external microbial stimuli), senescent mice exhibited increased and prolonged IL-1α/β reactions.23 These illustrate IL1 as a key mediator of niche inflammatory damage to HSC. Conversely, neutralizing transforming growth factor (TGF) -β was found to reverse the age-related bias of HSCs towards megakaryocytic differentiation, leading to a greater generation of lymphoid progenitors and a more balanced lineage output of HSCs in transplantation experiments. In addition, inhibiting IL-6 improved the function of erythroid progenitors in aged mice.25 The results indicate that inflammaging is a key mediator of age-related HSC myeloid/ megakaryocyte differentiation biases.

HSC aging leads to a diminished capacity for self-renewal (Fig. 2), as shown by a significant increase in the number of mouse HSCs with age, but not a corresponding increase in the capacity of HSCs to undergo self-renewal. Studies in aged mouse HSCs have shown that older HSCs have overall reduced cell cycle activity.26,27 Notably, IFN-γ, a crucial pro-inflammatory cytokine, appears to have a dual role in regulating HSC proliferation. On the one hand, IFN-γ has been observed to stimulate HSC proliferation during infections.28,29,30 On the other hand, conflicting evidence has suggested that IFN-γ can hinder HSC regeneration by restricting self-renewal, rather than impacting quiescence or cell cycle progression.30,31,32,33

During inflammation, HSCs shift their energy metabolism from relying on anaerobic glycolysis to oxidative respiration.34,35 Accumulated reactive oxygen species (ROS) stress may trigger excessive DNA damage and HSC senescence and/or apoptosis.36 Binding to C-X-C motif chemokine ligand (CXCL) 12, C-X-C motif chemokine receptor (CXCR) 4 serves as a crucial mediator in numerous physiological and pathological processes, including inflammatory responses of the immune systems, regulation of hematopoiesis, induction of angiogenesis, as well as tumor invasion and metastasis.37 Mice with disrupted CXCR4 receptors experience a rise in endogenous production of ROS, which activates p38 mitogen-activated protein kinases (MAPK), triggers an increase in DNA double-strand breaks, and leads to apoptosis. As a result, there is a notable decline in the HSC repopulation potential.37,38 This depletion of HSC pools can be attributed to the elevated ROS levels, which are not related to the loss of quiescence in CXCR4-deficient HSCs. The CXCR4/CXCL12 axis has been found to limit apoptosis, DNA damage, and ROS elevation in HSCs by reducing mitochondrial oxidative stress.38 These findings suggest that inflammation could hasten the aging of HSCs and accelerate HSC functional decline (Fig. 2).

노화한 골수 줄기세포(HSC)의 주요 특징 중 하나는

골수성/메가카리오사이트 분화 편향의

증가입니다. 18

increased myeloid/megakaryocytic differentiation 

인간 혈액 생성 시스템 내에서의 노화는 빈혈, 골수성 종양 및 적응 면역 반응 감소와 같은 다양한 결핍 및 질환 상태와 연관되어 있습니다. 유사한 현상은 쥐에서도 관찰되며, 이는 혈액 생성 줄기 세포(HSC) 수준에서 발생하는 변화와 연관되어 있습니다. 그러나 이러한 연관성은 인간 혈액 생성에서는 덜 확립되어 있으며, 이는 본 연구에서 인간 혈액 생성 시스템의 가장 원시적인 부위의 특성을 발생 과정 전반에 걸쳐 상세히 규명하도록 유도했습니다. 또한 인간과 쥐의 노화 혈액 생성 과정 간의 유사성을 탐구하기 위해 노력했습니다. 인간 제대혈(CB)에서 젊은 및 노화된 골수(BM)로의 전환과 함께 후보 HSC의 빈도가 점차 증가하는 것을 관찰했습니다. 이는 림프구 생성 감소 및 증식 잠재력 저하와 같은 기능적 장애와 동반되었습니다. 인간 HSCs 하류에서는 연령에 따라 공통 림프구 전구세포(CLPs)의 수준이 감소하고, 거대혈소판/적혈구 전구세포(MEPs)의 빈도가 증가하는 현상을 관찰했습니다. 이는 노화된 인간 HSCs에서 계통 관련 유전자 발현 패턴의 변화와 연관될 수 있습니다. 이러한 결과는 쥐에서도 유사하게 관찰되었습니다. 따라서 본 연구 결과는 인간 혈액 생성 과정에서도 연령 관련 변화가 HSC 풀에 영향을 미치며, 특히 거대핵세포/적혈구 계통으로의 편향이 두드러진다는 점을 뒷받침하며, 혈액 세포 시스템의 노화 메커니즘에 보존된 기전이 존재함을 시사합니다.

노화 과정은 최근 몇 년간 연구자들의 관심을 점점 더 끌고 있습니다. 이는 전 세계 평균 수명의 지속적인 증가와 밀접한 관련이 있습니다. 동시에 노화 관련 질환의 유병률도 증가하고 있습니다[1]. 노인들은 혈액 세포 시스템의 변화, 예를 들어 적응 면역 반응 감소[2], 빈혈 발생률 증가[3, 4], 골수 질환 위험 증가[5] 등을 자주 나타냅니다. 최근 연구 결과는 생리적 노화의 기초 과정이 암[6]과 같은 다른 질환의 병리적 사건과 유사할 수 있음을 시사합니다. 따라서 노화 과정에 대한 깊은 이해는 노화 연구 분야뿐만 아니라 노화 유사 증상을 보이는 질환을 가진 젊은 개인에게도 이점을 제공할 수 있습니다.

혈액 생성 시스템 내의 노화 관련 증상은 골수(BM) 미세환경 변화[7–9]와 같은 세포 외적 변화에 의해 영향을 받을 수 있습니다. 그러나 쥐에서 혈액 생성 줄기세포(HSCs) 자체의 내인성 변화가 혈액학적 노화의 주요 원동력이라는 증거가 풍부합니다. 이는 기능적, 유전적, 에피게놈적 변화 등을 포함합니다 [10–16]. 쥐에서 HSCs의 빈도는 증가하지만, 세포당 증식 능력은 감소합니다 [10–12, 17]. 여러 보고서에 따르면, 노화된 쥐의 HSCs는 골수계-림프계 출력 증가, 흔히 골수 편향(My-bi)으로 불리지만, 세포당 골수계 세포 형성 능력도 젊은 HSCs에 비해 감소합니다 [14, 18]. 이러한 관찰은 노화된 HSC 부위 내에서 My-bi HSC 빈도가 증가하는 동시에 림프구 편향(Ly-bi) HSC 빈도가 감소하는 연령 관련 클론 이동과 연관되어 있을 것으로 추정됩니다 [18–20], 그러나 이러한 변화는 일부 정도는 품종 특이적일 수 있습니다 [18]. 어쨌든, 마우스 HSC 노화에 따른 계통 편향은 골수 특이적 유전자 발현 증가와 림프구 특이적 유전자 발현 감소와 연관되어 있습니다 [11–15, 18], 그러나 이전 전사체 분석의 대부분은 계통 관련 유전자의 선택과 수동적 정리에 기반을 두고 있습니다. 반면, 더 객관적으로 정의된 계통 연관 전사 프로그램을 기반으로 한 단일 HSC의 전사체 분석은 노화된 마우스 HSC에서 골수 편향(My-bi)이 아닌 분자적 및 기능적 혈소판 편향을 보여주었습니다 [21].

인간 HSC 및 전구세포의 노화는 마우스 시스템만큼 광범위하게 특성화되지 않았지만, 몇 가지 유사점은 노화 특성이 종 간에 적어도 일부는 보존될 수 있음을 시사합니다. 예를 들어, HSC 증식과 클론 다양성은 제대혈(CB)과 노화된 골수(BM) 사이에서 감소합니다[22–24]. 또한 기증자 연령은 임상 골수 이식 결과에 영향을 미치지만, 이는 주로 HSC 성능 감소만으로 설명될 수 없습니다[25–29]. 제한된 수의 개인으로부터 수집된 노화된 인간 혈액 줄기 및 전구 세포(HSPC)의 빈도와 기능을 직접 평가한 결과, 쥐에서의 이전 연구 결과와 유사한 특징이 관찰되었습니다. 이는 골수-림프구 출력 비율 증가와 재구성 잠재력 감소 등을 포함하지만, 이 결과는 논란의 여지가 있습니다 [31].

본 연구에서는 인간 HPSC의 연령 관련 변화를 특성화하고 쥐에서의 유사 연구 결과와 비교했습니다. 골수계열을 거대핵세포/적혈구계열과 과립구/대식세포계열로 분리함으로써, 인간과 쥐의 노화 HSC에서 거대핵세포/적혈구계열 편향의 분자적 기전을 규명했습니다. 또한, 노화된 쥐와 인간 HSC에서 공통적으로 및 차등적으로 조절되는 유전자 집합을 식별했으며, 이는 HSC 노화 과정에서 종 간 보존된 유전자 발현 패턴을 시사합니다.

그란룰로사이트 콜로니 자극 인자 (G-CSF),

대식세포 콜로니 자극 인자 (M-CSF),

그란룰로사이트-대식세포 콜로니 자극 인자 (GM-CSF),

인터루킨 (IL)-1, IL-3, IL-6, TNF-α, 인터페론 (IFN) 및 Flt3 리간드 등

다양한 염증성 사이토킨과 성장 인자가 

혈액 줄기/전구 세포(HSPC)의 골수계 세포로의 분화를 림프계 세포보다 촉진하여

골수계와 림프계 분화의 불균형을 초래합니다.19,20,21

예를 들어,

노화 마우스의 골수에 축적된 플라즈마 세포는

IL-1 및 TNF-α와 같은 염증성 사이토카인의 피드백 루프를 생성하여

HSC의 골수계 분화 편향을 촉진합니다. 22

최근 연구에 따르면

노화 마우스의 골수 세포는 더 많은 IL-1α/β를 분비하며,23

손상된 내골막은 골수 중심부에서 염증을 유발하여 혈액 생성 재생을 방해하기 위해 IL-1β를 생성합니다.24

생체 내 자극(외부 미생물 자극을 모방한 리포폴리사카라이드)에 노출된 노화 마우스는 IL-1α/β 반응이 증가하고 지속되었습니다. 23 이는 IL-1이 HSC에 대한 미세환경 염증 손상의 핵심 매개체임을 보여줍니다. 반면, 변형 성장 인자(TGF)-β를 중화시키면 HSC의 연령 관련 거대핵세포 분화 편향을 역전시켜 림프구 전구세포의 생성 증가와 HSC의 분화 라인 출력 균형을 회복시키는 것으로 나타났습니다. 또한, IL-6 억제는 노화 마우스의 적혈구 전구세포 기능을 개선했습니다.25

이 결과는

염증성 노화가

HSC의 골수/거대핵세포 분화 편향의 핵심 매개체임을 시사합니다.

HSC 노화는 자기 재생 능력의 감소(그림 2)를 초래하며,

이는 쥐 HSC의 수량이 연령에 따라 유의미하게 증가하지만,

HSC의 자기 재생 능력은 이에 상응하지 않는 증가를 보이지 않습니다.

노화 마우스 HSC 연구에서 노화된 HSC는 전체적인 세포 주기 활동이 감소된 것으로 나타났습니다.26,27 특히, 중요한 프로염증성 사이토킨인 IFN-γ는 HSC 증식을 조절하는 이중 역할을 하는 것으로 보입니다. 한 편으로, IFN-γ는 감염 시 HSC 증식을 자극하는 것으로 관찰되었습니다.28,29,30 반면, 상반된 증거는 IFN-γ가 휴면 상태나 세포 주기 진행에 영향을 주기보다는 자기 재생 능력을 제한함으로써 HSC 재생에 방해가 될 수 있음을 제시했습니다.30,31,32,33

염증 시 HSCs는 에너지 대사 방식을

무산소 당분해에서 산소 호흡으로 전환합니다.34,35

축적된 활성 산소 종(ROS) 스트레스는

과도한 DNA 손상 및 HSC 노화 및/또는 아포토시스를 유발할 수 있습니다. 36

C-X-C 모티프 케모카인 리간드(CXCL) 12에 결합하는 C-X-C 모티프 케모카인 수용체(CXCR) 4는

면역계의 염증 반응, 혈액 생성 조절, 혈관新生 유도, 종양 침윤 및 전이 등

다양한 생리적 및 병리적 과정에서 중요한 매개체 역할을 합니다. 37

CXCR4 수용체가 손상된 마우스에서는 내인성 ROS 생산이 증가하며,

이는 p38 미토겐 활성화 단백질 키나제(MAPK)를 활성화시켜

DNA 이중 가닥 파열을 증가시키고

아포토시스를 유발합니다.

이로 인해 HSC 재증식 잠재력이 현저히 감소합니다.37,38

이 HSC 풀의 고갈은 CXCR4 결핍 HSC의 휴면 상태 상실과 무관한 ROS 수준 상승에 기인합니다. CXCR4/CXCL12 축은 미토콘드리아 산화 스트레스를 감소시켜 HSCs에서의 세포 사멸, DNA 손상, 및 ROS 증가를 억제하는 것으로 밝혀졌습니다.38 이러한 결과는 염증이 HSCs의 노화를 가속화하고 HSC 기능 저하를 촉진할 수 있음을 시사합니다(그림 2).

Neutrophils

The role of neutrophils throughout the inflammatory response involves activation, migration, and clearance of pathogens and damaged tissues. The age-related decline in neutrophil function has a substantial influence on the development and advancement of various age-related diseases. Neutrophil development and numbers do not appear to be systematically altered with advancing age (Fig. 2).

Immunosenescence of neutrophils occurs in a low-grade inflammatory environment, with specific abnormalities in their metabolism and function, including decreased phagocytic capacity,39 abnormalities in adhesion and chemotaxis,40,41 increased apoptosis,40,42 abnormal neutrophil trap network release,43 and abnormal toll-like receptor function.44 In addition, as the organism ages, the transcriptomic and epigenomic profiles of neutrophils undergo significant remodeling.45

Past studies have focused on changes in neutrophils maintained in culture for a few hours in vitro, as they defined neutrophil senescence as its phenotypic change from release into the bloodstream to disappearance in the absence of inflammation. Another phenotypic change observed in neutrophils during in vitro culture is the downregulation of CXCR2 (CXCL1 receptor), a potent neutrophil chelator that has been shown to promote the release of neutrophils into the circulation and migration to sites of inflammation.46,47 In mice, senescence can disrupt the normal movement of neutrophils across epithelial layers in injured tissues through a CXCL1-mediated mechanism, resulting in abnormal neutrophil trafficking and consequential damage to distant organs.48 CXCL1 can also attract neutrophils to the liver of older mice, where they generate ROS and trigger tissue senescence and inflammation.49 Therefore, the role of neutrophils in defending against inflammation and pathogens is greatly weakened during aging (Fig. 2).

중성구

중성구는

염증 반응 전반에 걸쳐 병원체 및 손상된 조직의 활성화, 이동, 제거에 관여합니다.

중성구 기능의 연령 관련 감소는

다양한 연령 관련 질환의 발생 및 진행에 상당한 영향을 미칩니다.

중성구의 발달 및 수는 연령이 증가함에 따라 체계적으로 변화하지 않는 것으로 보입니다(그림 2).

중성구의 면역노화는 저등급 염증 환경에서 발생하며, 대사 및 기능의 특정 이상을 포함합니다. 이는 식균 능력 감소,39 부착 및 화학유인 반응 이상,40,41 세포사멸 증가,40,42 중성구 트랩 네트워크 방출 이상,43 및 Toll-like 수용체 기능 이상을 포함합니다.44 또한 유기체가 노화함에 따라 중성구의 전사체 및 에피게놈 프로파일은 상당한 재구조화를 겪습니다.45

과거 연구는 체외에서 몇 시간 동안 배양된 중성구의 변화를 주로 조사했으며, 중성구 노화를 혈류로 방출된 후 염증 없이 사라지는 현상으로 정의했습니다. 체외 배양 중 중성구에서 관찰된 또 다른 형질 변화는 중성구 방출과 염증 부위로의 이동을 촉진하는 강력한 중성구 결합 단백질인 CXCR2(CXCL1 수용체)의 발현 감소입니다. 46,47 쥐에서 노화는 CXCL1 매개 메커니즘을 통해 손상된 조직의 상피층을 가로지르는 중성구의 정상적인 이동을 방해하여 중성구 이동 장애와 결과적으로 원격 장기 손상을 초래합니다.48 CXCL1은 또한 노화된 쥐의 간으로 중성구를 유인하여 ROS를 생성하고 조직 노화와 염증을 유발합니다.49 따라서 노화 과정에서 염증과 병원체에 대항하는 중성구의 역할은 크게 약화됩니다(그림 2).

Monocytes/macrophages

Apart from neutrophils, macrophages act as the initial responders to infections and participate in identifying, engulfing, and breaking down cellular debris and pathogens. The deterioration of macrophage function is a critical contributor to immunosenescence, where the capability of macrophages to effectively clear senescent cells from tissues reduces with aging (Fig. 2). Aged macrophages exhibit changes like reduced autophagy50 and a defect in their ability to fight viral infections.51

Aged macrophages display a noteworthy increase in SASP components, such as TNF-α, IL-6, and IL-1β. Furthermore, the ERCC1 gene deletion, which accelerates immune aging, was found to be responsible for the failure to excise the coding sequence for the DNA repair protein ERCC1 (ERCC1 gene deletion accelerates immune deficiency).10 Of particular importance, the anti-inflammatory cytokine IL-10 exhibited a decrease.52 This may lead to a tissue environment more prone to fibrosis, as IL-10 has been found to possess anti-fibrotic properties by suppressing pro-fibrotic molecules, including TGF-β.53,54 Besides, senescent macrophages show significant upregulation of both cell-cycle checkpoint inhibitors p16INK4a and p21CIP1 in a mouse model with deficiency in repairing DNA damage10 and downregulate both glycolysis and mitochondrial oxidative phosphorylation, which leads to an energy-depleted state that impairs the functioning of macrophages (Fig. 2).55

단핵구/대식세포

호중구와 별도로,

대식세포는 감염에 대한 초기 반응자로서

세포 파편 및 병원균을 식별, 포획 및 분해하는 역할을 합니다.

대식세포 기능의 저하는

면역 노화에 중요한 요인으로,

노화에 따라 조직에서 노화 세포를 효과적으로 제거하는 대식세포의 능력이 저하됩니다 (그림 2).

노화된 대식세포는

자가포식 감소50 및 바이러스 감염에 대항하는 능력 저하와 같은 변화를 보입니다.51

노화된 대식세포는

TNF-α, IL-6, IL-1β와 같은 SASP 성분의 현저한 증가를 보입니다.

또한 면역 노화를 가속화하는 ERCC1 유전자 결손이

DNA 수리 단백질 ERCC1의 코딩 서열 제거 실패와 관련이 있다는 것이

밝혀졌습니다(ERCC1 유전자 결손은 면역 결핍을 가속화합니다).10

특히 중요한 점은

항염증 사이토킨 IL-10의 감소가 관찰되었다는 것입니다. 52

이는 IL-10이 TGF-β를 포함한 섬유화 촉진 분자를 억제함으로써

섬유화 억제 특성을 갖는 것으로 알려져 있어,

섬유화에 더 취약한 조직 환경으로 이어질 수 있습니다. 53,54

또한, DNA 손상 수리 결핍 마우스 모델에서 노화 대식세포는 세포 주기 체크포인트 억제제 p16INK4a와 p21CIP1의 발현이 유의미하게 증가했으며,10 글리코lysis와 미토콘드리아 산화 인산화 모두를 억제하여 에너지 고갈 상태를 유발해 대식세포의 기능을 저해합니다(그림 2).55

Natural killer (NK) cells

NK cells are fundamental cells of the innate immune system and are regarded as the primary defense mechanism for human health. Recent findings indicate that NK cells play a central role in the immune surveillance of aging cells, and that dysfunctional NK cell activity is associated with infections, malignant tumors, inflammatory diseases, and an increased burden of aging cells with advancing age.56 While age does not seem to affect the number of NK progenitors in the peripheral blood or bone marrow,57 most studies suggest that the aging process causes an elevation of the overall number of NK cells in older adults.58,59 However, this increase in NK cell number is accompanied by a decline in their ability to proliferate and kill targets (Fig. 2).60,61,62 Specifically, there tends to be a decrease in the proportion of immature CD56 bright NK cells and an increase in the percentage of CD56 dim NK cells.61,63 CD56 dim cells produce many cytokines and mainly play an immunomodulatory role. They also account for more than 90% of NK cells, the majority of which are cytotoxic and have strong killing activity. Moreover, changes in the expression‎ of NKp30, NKp46, and DNAM1 (NK activation receptors) in the elderly can impair the immune surveillance function of NK cells.64,65,66 Due to age-related functional decline, NK cells from younger donors exhibit a greater potential for expansion than those from older donors when subjected to in vitro stimulation with IL-2, underscoring the susceptibility of NK cells to age-related dysfunction.61 Also, the signs of reduced NK cell effector functions, such as decreased cytotoxicity, as well as lower expression‎ of perforin and granzyme and reduced secretion of IFN-α and IFN-γ but more IL-1, IL-4, IL-6, IL-8, IL-10, and TNF-α are identified.67,68 Besides, with increasing donor age, the frequency of T cell precursors in CD34+Lin- cells tends to decrease, while the frequency of NK/T cell precursors tends to increase.69 This suggests that the lymphoid differentiation potential of peripheral blood precursor cells shifts from T cells to NK/T cells with age, meaning that more HSCs differentiate into NK/T cells. Meanwhile, a notable rise in the quantity of both NK and NKT cells occurs after the age of 60 (Fig. 2).70

자연살해(NK) 세포

NK 세포는

선천성 면역계의 기본 세포로,

인간 건강의 주요 방어 메커니즘으로 간주됩니다.

최근 연구 결과는

NK 세포가 노화 세포의 면역 감시에 중심적인 역할을 하며,

기능 장애를 보이는 NK 세포 활동이

감염, 악성 종양, 염증성 질환, 그리고

연령 증가에 따른 노화 세포의 부담 증가와 연관되어 있음을 보여줍니다.56

연령은 말초 혈액이나 골수 내 NK 전구세포의 수에 영향을 미치지 않는 것으로 보이지만,57 대부분의 연구는 노화 과정이 노인에서 전체 NK 세포 수의 증가를 유발한다는 것을 제시합니다. 58,59 그러나 이 NK 세포 수의 증가는 증식 능력과 표적 세포 살상 능력의 감소와 동반됩니다(그림 2).60,61,62 구체적으로, 미성숙한 CD56 밝은 NK 세포의 비율이 감소하고 CD56 어두운 NK 세포의 비율이 증가하는 경향이 있습니다.61,63 CD56 어두운 세포는 많은 사이토카인을 생성하며 주로 면역 조절 역할을 합니다. 또한 이들은 NK 세포의 90% 이상을 차지하며, 대부분 세포독성 기능을 가지고 강한 살상 활성을 나타냅니다.

또한 노인에서 NKp30, NKp46, DNAM1(NK 활성화 수용체)의 발현 변화는 NK 세포의 면역 감시 기능을 저하시킬 수 있습니다.64,65,66 연령 관련 기능 저하로 인해 젊은 기증자의 NK 세포는 IL-2로 체외 자극을 받았을 때 노인 기증자의 NK 세포보다 확장 잠재력이 더 높으며, 이는 NK 세포가 연령 관련 기능 장애에 취약함을 강조합니다. 61 또한 NK 세포의 효과기 기능 감소 징후로 세포독성 감소, 퍼포린 및 그라자임 발현 감소, IFN-α 및 IFN-γ 분비 감소, 반면 IL-1, IL-4, IL-6, IL-8, IL-10 및 TNF-α 분비 증가가 확인되었습니다. 67,68 또한 기증자 연령이 증가함에 따라 CD34+Lin- 세포 내 T 세포 전구체의 빈도는 감소하는 반면, NK/T 세포 전구체의 빈도는 증가하는 경향이 있습니다.69 이는 말초 혈액 전구 세포의 림프구 분화 잠재력이 연령에 따라 T 세포에서 NK/T 세포로 이동함을 의미하며, 이는 더 많은 HSCs가 NK/T 세포로 분화함을 시사합니다. 한편, 60세 이후에는 NK 세포와 NKT 세포의 양이 유의미하게 증가합니다(그림 2).70

B cells

B cells always work as antibody producers have an essential role in immunity.71 Age-related changes in B cell composition are the main reason for decreased antibody response to vaccination and infection in older adults (Fig. 2). Lymphopoiesis of B cells continues during the life cycle. The output of B cells is severely affected by changes in the microecology of the bone marrow, such as decreased pro-B cell-survival cytokine IL-7 level.72 The number of B-cell precursors and antibody-producing plasma cells in mouse and human bone marrow decreases with age.73 Further, the proliferative potency of lymphoid progenitor is also impaired by ageing, while that of myeloid progenitor does not changes.74 Different from mice, as individuals age, there is a decline in the proportion and absolute number of B cells in the peripheral blood.75,76 Especially, the aging process is associated with a rise in the proportion of late-stage exhausted memory B cells,77 while the percentage of memory B cells that exhibit a positive correlation with influenza vaccine responses significantly decreases with age.70,78 Furthermore, the number of B cells mobilized after antigenic stimulation is only 1/10 to 1/50 that of normal adult animals in the elderly. Similarly, the seropositive protection rate in those aged 60-74 years after influenza vaccination was 41% to 58%, decreasing to 29% to 46% for those 75 years or older. Meanwhile, a collapse in B cell diversity has been discovered.79 However, the elderly tend to exhibit an increase in autoantibodies, which can elevate the risk of developing autoimmune diseases.80

B cells not only produce antibodies, but also play regulatory effector functions in the development of memory T-cells (Fig. 2). Memory B cells are more preval‎ent in older adults and can produce various pro-inflammatory cytokines and chemokines such as IL-1α, IL-1β, IL-6, and TNF-α, suggesting their potential involvement in inflammatory disorders during inflammaging.81 Moreover, aging mice exhibit increased frequencies of age-associated B cells (ABCs) in their bone marrow, which secrete higher levels of TNF-α, a cytokine that impairs the generation of young pro-B cells.82 This observation suggests that bone marrow-resident ABCs may contribute to altered B cell development with age.

B 세포

B 세포는

항체 생산자로 항상 작용하며

면역 체계에서 필수적인 역할을 합니다.71

노화에 따른 B 세포 구성의 변화는

노인에서 백신 접종 및 감염에 대한 항체 반응 감소의 주요 원인입니다(그림 2).

B 세포의 림프구 생성은 생애 주기 동안 계속됩니다.

B 세포의 생산량은

골수 미세생태계의 변화,

예를 들어 프로-B 세포 생존 사이토킨 IL-7 수치 감소 등에 의해 심각하게 영향을 받습니다. 72

쥐와 인간의 골수에서 B 세포 전구체와 항체 생성 플라즈마 세포의 수는 연령이 증가함에 따라 감소합니다.73 또한, 림프계 전구체의 증식 능력은 노화로 인해 손상되지만, 골수계 전구체의 증식 능력은 변화하지 않습니다.74 쥐와 달리, 개인이 노화함에 따라 말초 혈액에서의 B 세포의 비율과 절대 수가 감소합니다. 75,76 특히 노화 과정은 후기 소진된 기억 B 세포의 비율 증가와 연관되어 있으며,77 인플루엔자 백신 반응과 양의 상관관계를 보이는 기억 B 세포의 비율은 연령이 증가함에 따라 유의미하게 감소합니다.70,78 또한 항원 자극 후 동원되는 B 세포 수는 노인에서 정상 성인 동물에 비해 1/10에서 1/50로 감소합니다. 同様に, 인플루엔자 백신 접종 후 60~74세 연령층의 항체 양성 보호율은 41%~58%였으며, 75세 이상에서는 29%~46%로 감소했습니다. 한편, B 세포 다양성의 급격한 감소가 발견되었습니다.79 그러나 노인들은 자가항체 증가 경향을 보이며, 이는 자가면역 질환 발병 위험을 높일 수 있습니다.80

B 세포는

항체를 생성할 뿐만 아니라

기억 T 세포의 발달 과정에서 조절 효과 기능을 수행합니다(그림 2).

기억 B 세포는

노인에서 더 많이 존재하며

IL-1α, IL-1β, IL-6, TNF-α와 같은 다양한 염증성 사이토킨과 케모카인을 생성할 수 있어

염증성 노화(inflammaging) 과정에서 염증성 질환에 관여할 가능성이 있습니다. 81

또한 노화 마우스의 골수에서는 연령 관련 B 세포(ABCs)의 빈도가 증가하며, 이 세포들은 젊은 프로-B 세포의 생성을 방해하는 사이토킨인 TNF-α를 더 높은 수준으로 분비합니다.82 이 관찰 결과는 골수 거주형 ABCs가 연령에 따른 B 세포 발달 변화에 기여할 수 있음을 시사합니다.

T cells

As fighters of pathogens, their dysfunction makes the mice less resistant to infection and get muscle atrophy. These dysregulated T cells even release many inflammatory molecules to accelerate aging,83 which emphasizes the role of T cells in aging. As a crucial immune cell type, T cell replenishment is achieved by the export from the thymus and self-renewal of peripheral naive T cells. In general, CD4 T cells are adaptable to the challenges of aging and keep naive-memory imbalance to a minor level. Compared with CD4 naive cells, the naive-memory imbalance in CD8 T cells is considerable. A decline in the number of circulating naive CD8 T cells is the most significant and consistently observed marker of immunosenescence in healthy older adults. Like CD4 T cells, BATF/IRF4 also promotes the transformation of naive CD8 T cells to effector CD8 T cells, which upregulates transcription factors related to effector functions, including T-bet, Runx3, and Blimp-1.84

With aging, the number of T helper cells (Th) and T regulatory cells (Treg) increases. The levels of cytokines secreted by Th1 and Th2 cells diminishes with age, making the body less able to defend itself against external pathogens. Elderly individuals exhibit increased expression‎ of TGF-β receptor 3 (TGFβR3) on naive CD4 cells. This leads to the activation of a transcription factor network that includes PU.1, BATF, and IRF4, ultimately resulting in a preference for Th9 differentiation.85,86 The increased Th9 leads to the increased secretion of the signature cytokine IL-9, which mediates various inflammatory responses and is involved in the differentiation of autoimmune diseases and inflammatory diseases.85 Although Treg cells increase in number with age, their suppressing capability declines significantly, which may contribute to inflammation in the elderly.87,88 At the molecular level, the damage to signal transduction, such as decreased CD28-mediated JNK kinase and Raf-1/MEK/ERK kinase activation, results in a hypo-responsiveness of T cell receptor (TCR) signal transduction.87 Meanwhile, effector memory CD45RA (EMRA) CD8 T cells show significant SASP, including high levels of IL-18 and disintegrin and metalloproteinase 28 (ADAM28, a proteinase involved in the cleavage of membrane-bound TNF-α).89,90 However, it is noteworthy that the cell cycle of EMRA CD8 T cells is partially reversible, which is different to senescent T cells.91

In old people, highly differentiated T cells, especially memory T cells display the loss of co-stimulatory molecules such as CD27/28, representing an earlier stage of senescence or exhaustion.92,93 Exhausted T cells display several hallmarks similar to aging ones, such as mitochondrial dysfunction94 and epigenetic dysregulation.95 Traditionally, it is believed that Exhausted T cells lack the function of secreting inflammatory, anti-inflammatory, and cytotoxic effector molecules.96 However, Denis et al. have recently substantiated that exhausted GZMK-expressing CD8 T cells can accelerate the inflammatory phenotypes.97

In the peripheral blood lymphocyte subsets of healthy adults in different ages, it was found that the decreased naive CD4 and CD8 T cell number, increased memory CD4 or CD8 T cell number, and decreased CD28 expression‎ on T cells.70 Numerous studies have shown a close association between increased stimulation by various antigens in vitro, especially cytomegalovirus (CMV) infection, and an increase in effector memory T cells,98 resulting in the activation of naive lymphocytes into memory lymphocytes and their long-term presence in vivo.13,99 This process leads to an increased number of memory CD4 and CD8 T lymphocytes with age, and a decrease of TCR diversity in naive T cells, which suppresses the responsiveness of T cells to neoantigens (Fig. 2).

In summary, as the body ages, most immune cells exhibit senescent characteristics, which manifests internally as difficulty in clearing senescent/damaged cells and externally as weakening of the body’s resistance.

T 세포

병원체와의 싸움에서 중요한 역할을 하는 T 세포의 기능 장애는

쥐의 감염 저항력을 감소시키고

근육 위축을 유발합니다.

이러한 조절이 깨진 T 세포는

노화를 가속화하는 많은 염증성 분자를 방출하며,83

이는 T 세포가 노화에 미치는 역할을 강조합니다.

면역 세포의 중요한 유형인 T 세포의 보충은

흉선에서 배출되고 주변 조직의 미성숙 T 세포의 자기 재생에 의해 이루어집니다.

일반적으로 CD4 T 세포는 노화의 도전 요인에 적응하며

미성숙-기억 세포의 불균형을 최소 수준으로 유지합니다.

CD4 미성숙 세포와 비교할 때 CD8 T 세포의 미성숙-기억 세포 불균형은 상당합니다. 순환하는 순수 CD8 T 세포의 수는 건강한 노인에서 면역 노화의 가장 중요하고 일관되게 관찰되는 지표입니다. CD4 T 세포와 마찬가지로 BATF/IRF4도 순수 CD8 T 세포를 효과기 CD8 T 세포로 전환시켜 T-bet, Runx3, Blimp-1 등 효과기 기능과 관련된 전사 인자의 발현을 증가시킵니다.84

노화 과정에서 T 보조 세포(Th)와 T 조절 세포(Treg)의 수가 증가합니다. Th1 및 Th2 세포가 분비하는 사이토카인의 수준은 연령에 따라 감소하여 신체는 외부 병원체에 대한 방어 능력이 저하됩니다. 노인에서는 naive CD4 세포에서 TGF-β 수용체 3(TGFβR3)의 발현이 증가합니다. 이는 PU.1, BATF, IRF4를 포함한 전사 인자 네트워크의 활성화를 유발하여 최종적으로 Th9 분화 선호로 이어집니다.85,86 증가한 Th9는 자가면역 질환과 염증성 질환의 분화에 관여하는 다양한 염증 반응을 매개하는 특징적인 사이토킨 IL-9의 분비를 증가시킵니다. 85 Treg 세포는 연령과 함께 수량이 증가하지만 억제 능력이 크게 감소하며, 이는 노인에서의 염증에 기여할 수 있습니다.87,88 분자 수준에서 신호 전달 손상(예: CD28 매개 JNK 키나제 및 Raf-1/MEK/ERK 키나제 활성화 감소)은 T 세포 수용체(TCR) 신호 전달의 저반응성을 유발합니다. 87 한편, 효과기 기억 CD45RA (EMRA) CD8 T 세포는 IL-18과 디스인테그린 및 금속단백분해효소 28 (ADAM28, 막 결합형 TNF-α의 분해에 관여하는 단백질 분해효소)의 높은 수준을 포함한 SASP를 나타냅니다.89,90 그러나 EMRA CD8 T 세포의 세포 주기가 부분적으로 가역적이라는 점은 주목할 만하며, 이는 노화 T 세포와 다릅니다. 91

노인에서 고도로 분화된 T 세포, 특히 기억 T 세포는 CD27/28과 같은 공자극 분자의 상실을 보여 노화 또는 소진의 초기 단계를 나타냅니다. 92,93 소진된 T 세포는 노화 세포와 유사한 여러 특징을 나타내며, 미토콘드리아 기능 장애94 및 에피제네틱 조절 장애95 등이 포함됩니다. 전통적으로 소진된 T 세포는 염증성, 항염증성, 세포독성 효과 분자의 분비 기능을 상실했다고 여겨져 왔습니다.96 그러나 Denis 등97은 최근 GZMK를 발현하는 소진된 CD8 T 세포가 염증성 표현형을 가속화할 수 있음을 입증했습니다.

건강한 성인의 다양한 연령층에서 말초 혈액 림프구 하위 집합을 분석한 결과, 미성숙 CD4 및 CD8 T 세포 수의 감소, 기억 CD4 또는 CD8 T 세포 수의 증가, T 세포에서의 CD28 발현 감소가 관찰되었습니다. 70 다양한 항원, 특히 사이토메갈로바이러스(CMV) 감염에 의한 체외 자극 증가와 효과기 기억 T 세포의 증가 사이에 밀접한 연관성이 여러 연구에서 확인되었습니다.98 이는 naive 림프구를 기억 림프구로 활성화시키고 체내에서 장기적으로 존재하게 합니다. 13,99 이 과정은 연령에 따라 기억 CD4 및 CD8 T 림프구의 수가 증가하고, naive T 세포의 TCR 다양성이 감소하여 T 세포의 신항원(neoantigen)에 대한 반응성이 억제됩니다(그림 2).

요약하면, 신체 노화 과정에서 대부분의 면역 세포는 노화 특성을 나타내며, 이는 내부적으로는 노화/손상된 세포의 제거 어려움으로, 외부적으로는 신체 저항력의 약화로 나타납니다.

Inflammaging at the organ level

As a result of the effects of cellular senescence, chronic inflammation, and immunosenescence, the pathological aging of organs increases the level of inflammation and makes repair difficult, ultimately leading to diseases.10

Lymphoid organs

The primary lymphoid organs, including the bone marrow and thymus, are responsible for immune cell development. However, with advancing age, these organs undergo a functional decline, which results in compromised capability of replenishing the immune cell reservoir. Senescence of the lymphatic organs promotes immunosenescence and plays a key role in organ inflammaging.

Aged bone marrow promotes HSC-related immunosenescence

The bone marrow, which serves as the site of hematopoiesis, is a complex environment where bone cells and hematopoietic cells interact with each other. Recent studies have highlighted the importance of the aging bone marrow microenvironment as a key contributor to the aging process. One significant finding is that a higher percentage of senescent bone marrow mesenchymal stem cells (MSCs) have been observed in older individuals compared to younger individuals. This was determined by DNA damage, elevated ROS, and accumulation of SASP-expressing cells. The SASP-generated inflammatory environment can change the expression‎ profile of healthy MSCs and disrupt the expression‎ of factors indispensable for lymphocyte survival (Table 1).100,101,102 Senescent MSCs generating inflammatory factors further impair the function and clonogenicity of young HSCs. Aging has been linked to several hematopoietic system-related issues, such as an increased occurrence of anemias, compromised adaptive immune responses,103 and a higher susceptibility to myelodysplastic and myeloproliferative disorders (Fig. 3).104

장기 수준의 염증성 노화

세포 노화, 만성 염증, 면역 노화의 영향으로 인해

장기의 병리적 노화는

염증 수준을 높이고 회복을 어렵게 하여

결국 질병으로 이어집니다.10

림프계 장기

골수 및 흉선과 같은 주요 림프계 장기는

면역 세포 발달을 담당합니다.

그러나 노화가 진행됨에 따라 이러한 장기는 기능적 퇴화를 겪으며,

이는 면역 세포 저장고의 보충 능력을 저하시킵니다.

림프계 장기의 노화는

면역 노화를 촉진하며,

장기 염증 노화(inflammaging)에 핵심적인 역할을 합니다.

노화된 골수는 HSC 관련 면역 노화를 촉진합니다

골수는 혈액 생성 장소로, 골세포와 혈액 생성 세포가 상호작용하는 복잡한 환경입니다. 최근 연구들은 노화된 골수 미세환경이 노화 과정의 주요 요인 중 하나임을 강조했습니다. 특히, 노인에서 젊은 사람에 비해 노화된 골수 중간엽 줄기세포(MSCs)의 비율이 높다는 점이 주목되었습니다. 이는 DNA 손상, 활성산소종(ROS) 증가, SASP 발현 세포의 축적에 의해 확인되었습니다. SASP에 의해 생성된 염증 환경은 건강한 MSC의 발현 프로필을 변화시키고 림프구 생존에 필수적인 인자의 발현을 방해합니다(표 1).100,101,102 노화 MSC가 생성하는 염증 인자는 젊은 HSC의 기능과 클론 형성 능력을 더욱 손상시킵니다. 노화는 빈혈 발생 증가, 적응 면역 반응 저하,103 골수이형성 및 골수증식 장애에 대한 취약성 증가 등 혈액 생성 시스템과 관련된 여러 문제와 연관되어 있습니다(그림 3).104

Table 1 Senescence-associated secretory phenotype (SASP) list

Full size table

Fig. 3

Aging-organ atlas.

Aging manifests as a decline in organ function and an increased susceptibility to diseases. Organs are mainly divided into immune organs, sterile organ, and others. Functional changes in cells are shown in each organ

Full size image

The aging of bone tissue inevitably affects HSCs. With age, red bone marrow is gradually replaced by fat cells, leading to yellow bone marrow formation that inhibits hematopoietic function.105 The decreased secretion of nutrient factors by bone marrow stromal cells can result in an enhanced differentiation of HSCs into myeloid cells and a reduced differentiation into lymphocytes. This imbalance in myeloid/lymphoid differentiation is one of the manifestations of HSC aging.105,106,107 Importantly, aged HSCs tend to differentiate more towards myeloid cells, while their ability to support lymphoid cell maturation decreases. This leads to a reduction in the number of precursors for T and B cells with increasing age.108,109 Taken together, with aging, the number of HSCs increases, while their function including self-renewal and clonogenicity, decreases. In addition to the HSC changes mentioned above, aging marrow also has decreased Wnt signaling and the accumulation of senescent cells and inflammatory cytokines.110

골 조직의 노화는

HSCs에 불가피하게 영향을 미칩니다.

연령이 증가함에 따라

적색 골수 조직이 점차 지방 세포로 대체되어

골수 기능을 억제하는 황색 골수 형성이 발생합니다.105

골수 간질 세포의 영양 인자 분비 감소는 HSCs의 골수 세포로의 분화 촉진과 림프구로의 분화 감소로 이어질 수 있습니다. 골수성/림프구 분화 불균형은 HSC 노화의 주요 증상 중 하나입니다.105,106,107 특히, 노화된 HSCs는 골수성 세포로 분화하는 경향이 증가하며, 림프구 성숙을 지원하는 능력은 감소합니다. 이로 인해 연령이 증가함에 따라 T 세포와 B 세포의 전구체 수가 감소합니다.108,109 종합적으로, 노화 과정에서 HSC의 수는 증가하지만, 자기 재생 및 클론 형성 능력 등 기능은 감소합니다. 위에서 언급된 HSC 변화 외에도 노화된 골수는 Wnt 신호전달 감소, 노화 세포의 축적, 염증성 사이토카인의 증가를 동반합니다.110

Aged thymus promotes T cell-related immunosenescence

The thymus is a central T-lymphatic organ that produces functional initial T-lymphocytes and immune tolerance. In most mammals, aging is accompanied by degeneration of the thymus gland. In humans, thymocyte numbers and hormone secretion levels typically increase during early development and then decrease over time. In addition, the majority of functional cells are substituted with senescent fibroblasts and adipocytes, and stromal cells during thymus aging.88,111,112 In the aged mouse thymus, elevated levels of phosphorylated histone H2AX and the p53 binding protein suggest heightened oxidative stress and DNA damage, consequently leading to cellular senescence,113 providing support for the notion that the aging thymus exhibits a greater proportion of senescent cells.

Thymic degeneration results in reduced generation of new T-cells, an accumulation of memory T-cells, and a decline in the diversity of T-cell receptors. As a consequence, this leads to a weakened immune response and decreased overall immunity. It has been observed that apparent aging-associated alteration, especially a progressively reduced population of naive T cells, in murine T cell compartment during thymic involution.114 However, in human, there is a progressive loss of CD8+ naive T cells while, notably, a relatively stable naive CD4+ compartment is efficiently maintained via homeostatic proliferation.115,116,117

Consequently, both in mice and humans, age-related variations in the production of naive T cells from the thymus result in qualitative disparities in the overall T cell repertoire.118,119,120,121 In addition, it has been observed that naive T cells from older individuals exhibit reduced responsiveness to the superantigen toxic shock syndrome toxin-1 compared to younger individuals,122,123 which may be caused by low dual specificity phosphatase 6 levels in naive T cells, resulting in a rise in the threshold of TCR activation.

노화된 흉선은 T 세포 관련 면역 노화를 촉진합니다

흉선은 기능적인 초기 T 림프구를 생성하고 면역 관용을 조절하는 중심적인 T 림프계 기관입니다. 대부분의 포유류에서 노화는 흉선 조직의 퇴화와 동반됩니다. 인간에서 흉선 세포 수와 호르몬 분비 수준은 초기 발달 단계에서 증가한 후 시간이 지남에 따라 감소합니다.

또한, 흉선 노화 과정에서

기능적 세포의 대부분이

노화된 섬유아세포와 지방세포, 그리고 간질 세포로 대체됩니다.88,111,112

노화된 쥐의 흉선에서는 인산화된 히스톤 H2AX와 p53 결합 단백질의 증가가 관찰되며, 이는 산화 스트레스와 DNA 손상의 증가를 시사하며, 결국 세포 노화로 이어집니다.113 이는 노화된 흉선이 노화된 세포의 비율이 더 높다는 가설을 뒷받침합니다.

흉선 퇴화는

새로운 T 세포의 생성 감소, 기억 T 세포의 축적, T 세포 수용체의 다양성 감소로 이어집니다.

이로 인해 면역 반응이 약화되고 전체적인 면역력이 감소합니다.

흉선 퇴화 과정에서 쥐의 T 세포 부위에서 노화 관련 변화, 특히 미성숙 T 세포의 점진적 감소가 관찰되었습니다.114 그러나 인간에서는 CD8+ 미성숙 T 세포의 점진적 손실이 발생하지만, 주목할 점은 상대적으로 안정된 미성숙 CD4+ 부위가 항상성 증식을 통해 효율적으로 유지된다는 점입니다.115,116,117

따라서 쥐와 인간 모두에서 흉선에서 생성되는 naive T 세포의 연령 관련 변동은 전체 T 세포 레퍼토리의 질적 차이를 초래합니다. 118,119,120,121 또한, 노인에서 유래한 naive T 세포는 젊은 개인에 비해 슈퍼항원 독성 쇼크 증후군 독소-1에 대한 반응성이 감소한다는 것이 관찰되었으며,122,123 이는 naive T 세포 내 이중 특이성 인산화효소 6(dual specificity phosphatase 6) 수치 저하로 인해 TCR 활성화 임계값이 상승하기 때문일 수 있습니다.

Aged spleen promotes T and B cell-related immunosenescence

The spleen acts as a secondary lymphoid organ promoting immune defense and is the main pivotal organ for initiating the activities required for the adaptive immune responses. During the aging process, significant alterations occur in the cellular composition and microarchitecture of the spleen. The clear distinction between T-cell and B-cell areas within the white pulp becomes less defined, and there are noticeable changes in the organization and functionality of marginal zone macrophages, stromal cells, and marginal metallophilic macrophages.124,125

Furthermore, recent advancements in single-cell RNA sequencing studies have revealed that the proportion of T cells in the spleen decreases with age, while the relative abundance of plasma cells increases.126 Impaired migration of B cells and the phagocytic capacity of macrophages in the marginal zone can also be seen in aged spleens.127 Also, impaired function of microenvironment-mediated antigen-presenting cells was observed, which may provide an explanation for the observed delayed responses to stimulation even in T cells derived from young HSCs (Fig. 3).102,128,129

노화된 비장은 T 세포와 B 세포와 관련된 면역 노화를 촉진합니다

비장은 면역 방어를 촉진하는 2차 림프 조직으로, 적응 면역 반응을 시작하기 위해 필요한 활동을 유발하는 주요 핵심 기관입니다. 노화 과정에서 비장의 세포 구성과 미세 구조에 상당한 변화가 발생합니다. 백색 림프구 영역 내 T 세포와 B 세포 영역의 명확한 구분은 흐려지며, 주변 구역 대식세포, 간질 세포, 주변 금속 친화성 대식세포의 조직 구조와 기능에 눈에 띄는 변화가 발생합니다.124,125

또한 단일 세포 RNA 시퀀싱 연구의 최근 진전은 비장에서 T 세포의 비율이 연령에 따라 감소하는 반면, 플라즈마 세포의 상대적 풍부도가 증가함을 보여주었습니다. 126 노화된 비장에서 B 세포의 이동 장애와 주변 구역의 대식세포의 식작용 능력이 저하되는 현상도 관찰됩니다.127 또한 미세환경에 의해 조절되는 항원 제시 세포의 기능 저하가 관찰되었으며, 이는 젊은 HSCs에서 유래한 T 세포에서도 자극에 대한 지연된 반응이 관찰된 현상을 설명할 수 있습니다(그림 3).102,128,129

Aged lymph nodes promote immunosenescence

Lymph nodes serve as crucial sites where T cells and B cells reside and where immune responses are initiated, playing a vital role in establishing an effective immune response. However, the number, integrity, and functionality of lymph nodes undergo significant declines with age, as evidenced by previous studies.102,125 The exact cause of lymph node atrophy remains unknown; however, it can result in the deterioration of the microenvironment where immune cells reside, thereby negatively impacting immune function. Age-related alterations in cellularity and the functionality of different cell types within the lymph nodes have been extensively documented.130 Specifically, the number of fibroblastic reticular cells in lymph nodes diminishes, resulting in a compressed and less reticular stromal network.131 In addition, older individuals, aged 60 years and above, exhibit increased fat deposition and fibrosis in their lymph nodes.124,125 Moreover, stromal cells within aged lymph nodes exhibit reduced replication potential when stimulated and are unable to maintain a balance of naive T cells.126,127,131 The accumulation of senescent cells in lymph nodes, along with heightened inflammation, may negatively impact the migration and recruitment of immune cells, thereby serving as detrimental factors (Fig. 3).130

노화된 림프절은 면역 노화를 촉진합니다

림프절은 T 세포와 B 세포가 거주하고 면역 반응이 시작되는 중요한 장소로, 효과적인 면역 반응을 확립하는 데 필수적인 역할을 합니다. 그러나 이전 연구에서 입증된 바와 같이, 림프절의 수, 구조적 완전성, 기능은 연령에 따라 크게 감소합니다.102,125 림프절 위축의 정확한 원인은 아직 알려지지 않았지만, 이는 면역 세포가 거주하는 미세 환경의 악화를 초래하여 면역 기능에 부정적인 영향을 미칠 수 있습니다. 림프절 내 다양한 세포 유형의 세포 수와 기능에 대한 연령 관련 변화는 광범위하게 보고되었습니다.130 특히, 림프절 내 섬유모상 망상 세포의 수가 감소하여 압축되고 덜 망상적인 간질 네트워크가 형성됩니다.131 또한 60세 이상의 노인에서는 림프절 내 지방 침착과 섬유화가 증가합니다. 124,125 또한 노화된 림프절 내의 간질 세포는 자극 시 복제 잠재력이 감소하며, 미성숙 T 세포의 균형을 유지하지 못합니다.126,127,131 림프절 내 노화 세포의 축적과 염증의 증가는 면역 세포의 이동 및 모집에 부정적인 영향을 미쳐 유해 요인으로 작용할 수 있습니다(그림 3).130

Sterile organs

Brain

The main cause of brain aging appears to be neuroinflammation132 via aged brain cells and a weakened immune system. The process of brain aging significantly contributes to the decline of various cognitive functions, encompassing decreased speed of information processing, reduced capacity of working memory, impaired spatial memory, and diminished plasticity (Fig. 3).133

Aging of brain cells including neurons and glial cells (i.e., microglia and astrocytes) leads to the upregulation of inflammatory-related pathways, causing brain function weakness and increased inflammation damage. During the aging process, microglia gradually lose their ability to efficiently clear misfolded proteins that are linked to neurodegeneration. This impairment in protein clearance significantly contributes to the neuroinflammatory response observed in the brain, with microglia playing a central role in this process. Except for the supporting role, Shao et al. found that astrocytes can also be a mastermind of neuroinflammation, depending on the Dopamine D2 receptor (Drd2), normally an important brake on it.134 During aging, the level of Drd2 and its ligand dopamine both decline with high neuroinflammation in the brain. Subsequently, activated astrocytes produce SASP factors, such as IL-1β, IL-6, TNF-α, IFN-γ, COX-2, and other inflammatory factors (Table 1). In turn, these factors further promote astrocyte activation. The excessive production of pro-inflammatory mediators disrupts the intricate equilibrium necessary for the induction of long-term potentiation, leading to a decrease in the production of brain plasticity-related molecules such as BDNF and IGF-1, consequently impairing synaptic plasticity.135 Remarkably, even older adults without neurological impairments demonstrate a gradual escalation in neuroinflammation, characterized by elevated homeostatic levels of inflammatory cytokines and reduced production of anti-inflammatory molecules (Fig. 3).136

Immunosenescence and inflammaging can both contribute to neuroinflammation, resulting in impaired neuronal function and the accumulation of brain tissue damage.137,138 Consequently, various central nervous system disorders, including Alzheimer’s disease, Parkinson’s disease, and stroke, are characterized by degenerative neurological conditions.139

무균 장기

뇌

뇌 노화의 주요 원인은 노화된 뇌 세포와 약화된 면역 체계에 의한 신경염증132로 추정됩니다. 뇌 노화 과정은 정보 처리 속도 감소, 작업 기억 용량 감소, 공간 기억 장애, 가소성 감소 등 다양한 인지 기능 저하에 크게 기여합니다(그림 3).133

신경세포와 글리아 세포(즉, 미세아교세포와 별아교세포)를 포함한 뇌 세포의 노화는 염증 관련 경로의 활성화로 이어지며, 이는 뇌 기능 약화와 염증 손상의 증가를 초래합니다.

노화 과정에서 미세아교세포는 신경퇴화와 관련된 변형 단백질을 효율적으로 제거하는 능력을 점차 상실합니다. 이 단백질 제거 기능의 저하는 뇌에서 관찰되는 신경염증 반응에 크게 기여하며, 미세아교세포는 이 과정에서 중심적인 역할을 합니다.

지원 역할 외에도 Shao 등(2023)은 아스트로사이트가 도파민 D2 수용체(Drd2)에 따라 신경염증의 주동자가 될 수 있음을 발견했습니다. Drd2는 일반적으로 신경염증을 억제하는 중요한 역할을 합니다.134 노화 과정에서 Drd2와 그 리간드인 도파민의 수준은 뇌 내 높은 신경염증과 함께 감소합니다. 활성화된 아스트로사이트는 IL-1β, IL-6, TNF-α, IFN-γ, COX-2 등 SASP 인자 및 기타 염증 인자(표 1)를 생성합니다. 이 인자들은 다시 아스트로사이트 활성화를 촉진합니다. 과도한 염증 매개체의 생산은 장기적 강화(LTP) 유도 위해 필요한 복잡한 균형을 방해하여 BDNF 및 IGF-1과 같은 뇌 가소성 관련 분자의 생산을 감소시키며, 결국 시냅스 가소성을 손상시킵니다. 135 흥미롭게도 신경학적 장애가 없는 노인들도 염증성 사이토카인의 항상성 수준 증가와 항염증 분자 생산 감소로 특징지어지는 신경염증의 점진적 악화를 보여줍니다(그림 3).136

면역 노화(immunosenescence)와 염증성 노화(inflammaging)는 모두 신경염증에 기여하여 신경 세포 기능 장애와 뇌 조직 손상의 축적을 초래합니다.137,138 결과적으로 알츠하이머 병, 파킨슨 병, 뇌졸중 등 다양한 중추 신경계 장애는 퇴행성 신경학적 질환으로 특징지어집니다.139

Heart

Most cardiac tissue is composed of cardiomyocytes, cardiac fibroblasts, and macrophages. The aging process in the heart is characterized by the gradual occurrence of several hallmarks, including progressive cardiomyocyte hypertrophy, the gradual onset of cardiac fibrosis, and the presence of inflammation (Fig. 3).140

Hypertrophic cardiomyocytes, characterized by heightened oxygen and energy requirements, create a hypoxic environment of low oxygen levels. This imbalance in oxygen levels leads to the generation of excessive free radicals, which can potentially damage cellular components. In response to hypoxia, cardiomyocytes release pro-inflammatory cytokines and chemokines. These molecules stimulate an immune response and contribute to an increase in the number of macrophages within the left ventricle.140 In addition, because mature cardiomyocytes have a low rate of proliferation, the injured area in the aging heart is replaced by fibrotic scar tissue, resulting in organ failure.141

The main effector cells in cardiac fibrosis are activated myofibroblasts. Long-term inflammation promotes cardiac and vascular fibrosis. The cardioprotective effects of AMPK and GDF11 on cardiomyocytes have been extensively documented, and the decline in AMPK and GDF11 expression‎ associated with aging is likely a contributing factor to the heightened cardiac fibrosis observed during the aging process.142

In the steady-state heart, macrophages play a crucial role in eliminating senescent and dying cells, contributing to the normal homeostatic maintenance of the myocardium and facilitating tissue repair following injury. However, in the aging heart, macrophages recruited to the site of infarction exhibit a pro-inflammatory M1 phenotype initially, but subsequently transition to an anti-inflammatory M2 phenotype after myocardial infarction (MI). This phenotypic switch promotes angiogenesis and scar formation, aiding in the recovery process.143

In addition, vascular smooth muscle cells (VSMCs) play a crucial role in coordinating vascular function alongside endothelial cells, regulating blood pressure, vascular tone, and blood flow. However, during the aging process, the dysfunction and decline of VSMCs have a detrimental impact on the structural integrity of the aorta, ultimately leading to the development of transthoracic aortic aneurysms.142 Classical molecular IGF-1 signaling causes cardiac hypertrophy and heart failure.142 IGF-1 increases cellular senescence in VSMCs by inducing DNA damage and increasing ROS production via the p53 pathway.

심장

심장 조직의 대부분은 심근 세포, 심장 섬유아세포, 및 대식세포로 구성되어 있습니다. 심장의 노화 과정은 점진적으로 발생하는 여러 특징으로 특징지어지며, 이는 심근 세포의 점진적인 비대, 심장 섬유화의 점진적인 발생, 및 염증의 존재를 포함합니다(그림 3).140

비대화된 심근 세포는 산소와 에너지 요구량이 증가하여 저산소 환경을 생성합니다. 이 산소 농도의 불균형은 과도한 자유 라디칼의 생성을 유발하며, 이는 세포 구성 요소에 손상을 입힐 수 있습니다. 저산소 상태에 대응하여 심근 세포는 염증성 사이토카인과 케모카인을 분비합니다. 이 분자들은 면역 반응을 자극하고 좌심실 내 대식세포의 수를 증가시킵니다.140 또한 성숙한 심근 세포는 증식 속도가 낮기 때문에 노화 심장의 손상된 부위는 섬유화 흉터 조직으로 대체되어 장기 기능 장애를 초래합니다.141

심장 섬유화의 주요 효과 세포는 활성화된 미오피브로블라스트입니다. 장기적인 염증은 심장과 혈관의 섬유화를 촉진합니다. AMPK와 GDF11이 심근 세포에 미치는 심장 보호 효과는 광범위하게 보고되었으며, 노화에 따른 AMPK와 GDF11 발현의 감소는 노화 과정에서 관찰되는 심장 섬유화 증가의 주요 요인 중 하나일 가능성이 있습니다.142

정상 상태의 심장에서 대식세포는 노화 및 사멸 세포를 제거하는 데 중요한 역할을 하며, 심근의 정상적인 항상성 유지와 손상 후 조직 복구를 촉진합니다. 그러나 노화 심장에서 심근경색 부위로 모집된 대식세포는 초기에는 염증성 M1 형질을 나타내지만, 심근경색(MI) 후에는 염증 억제성 M2 형질로 전환됩니다. 이 형질 전환은 혈관新生과 흉터 형성을 촉진하여 회복 과정을 돕습니다.143

또한, 혈관 평활근 세포(VSMC)는 내피 세포와 함께 혈관 기능을 협응하고, 혈압, 혈관 긴장도 및 혈류를 조절하는 중요한 역할을 합니다. 그러나 노화 과정에서 VSMCs의 기능 장애와 감소는 대동맥의 구조적 안정성에 악영향을 미쳐 결국 흉부 대동맥 동맥류의 발생으로 이어집니다.142 고전적인 분자 IGF-1 신호전달은 심근 비대 및 심부전을 유발합니다.142 IGF-1은 p53 경로를 통해 DNA 손상을 유발하고 활성산소종(ROS) 생성을 증가시켜 VSMCs의 세포 노화를 촉진합니다.

Kidney

As individuals age, the kidneys undergo various structural impairments, such as fibrosis, and experience functional issues, including mitochondrial dysfunction (Fig. 3).144,145,146 Moreover, older individuals become more susceptible to acute kidney injury (AKI) and chronic kidney disease (CKD).123,147 Age-related alterations in multiple cell types, such as tubular epithelial cells, resident and circulating leukocytes, contribute to kidney injury. Proximal tubular cells depend on autophagy to effectively eliminate defective mitochondria and other organelles under both normal and pathological conditions.148,149 However, during aging, their diminished proliferative capacity leads to impaired clearance abilities.150

Aging in the kidneys is associated with various physiological changes, including chronic low-grade inflammation. This inflammatory state, often referred to as inflammaging, has been observed to have detrimental effects on the kidneys. Chronic low-grade inflammation in the kidneys can impair the normal repair mechanisms that occur following injury. This inflammation hampers intrinsic cellular repair mechanisms following injury and promotes immunosenescence and organ damage.151,152 Elderly individuals exhibit immunological phenotypes characterized by reduced numbers of naive lymphocytes, increased pro-inflammatory T cells, and diminished phagocytic activity in monocyte lineage cells, similar to CKD patients. These alterations in the kidneys form the basis for preval‎ent pathological conditions that are commonly observed in both elderly individuals and patients with CKD.123

신장

개인이 노화함에 따라 신장은 섬유화 등 다양한 구조적 손상을 겪으며, 미토콘드리아 기능 장애(그림 3)를 포함한 기능적 문제를 경험합니다.144,145,146 또한 노인은 급성 신장 손상(AKI)과 만성 신장 질환(CKD)에 더 취약해집니다.123,147 신장 내 다양한 세포 유형(예: 관상 상피 세포, 거주 및 순환 백혈구)의 노화 관련 변화가 신장 손상에 기여합니다. 근위 세뇨관 세포는 정상 및 병리학적 조건에서 결함이 있는 미토콘드리아 및 기타 세포 기관을 효과적으로 제거하기 위해 자가포식에 의존합니다.148,149 그러나, 노화 과정에서 증식 능력이 저하되어 제거 능력이 약화됩니다.150

신장의 노화는 만성 저급 염증 등 다양한 생리적 변화와 관련이 있습니다. 흔히 염증성 노화라고 하는 이 염증 상태는 신장에 해로운 영향을 미치는 것으로 관찰되었습니다. 신장의 만성 저등급 염증은 손상 후 발생하는 정상적인 복구 메커니즘을 손상시킵니다. 이 염증은 손상 후 내재적 세포 복구 메커니즘을 방해하고 면역 노화 및 장기 손상을 촉진합니다.151,152 노인들은 CKD 환자와 유사하게 미성숙 림프구 수 감소, 염증성 T 세포 증가, 단핵구 계통 세포의 식작용 활성 감소 등 면역학적 특징을 나타냅니다. 신장에서 발생하는 이러한 변화는 노인 및 CKD 환자에서 흔히 관찰되는 주요 병리적 상태의 기반을 형성합니다.123

Liver

Aging raises the risk of chronic liver disease and liver fibrosis, which is highly related to hepatic stellate cells, hepatocytes, and macrophages. Liver cells initially activate compensatory mechanisms in response to time-dependent damage caused by aging, which can lead to the development of pathologies of the liver if overstimulated.153 Activated hepatic stellate cells are the major functional population during liver fibrogenesis.154 During senescence, their replication, immune-recruiting signals, and clearance are important for the regulation of liver fibrogenesis.155 An illustration of the contribution of senescent hepatocytes to hepatic stellate cell activation and liver fibrogenesis is evident in p53-deficient mice with nutrition-induced steatohepatitis. It was discovered that these mice displayed reduced levels of hepatocyte p21, as well as decreased activation of hepatic stellate cells and expression‎ of fibrotic markers such as SMA and collagen.156 This finding supports the involvement of senescent hepatocytes in the activation of hepatic stellate cells and the development of liver fibrosis. Furthermore, M2 macrophages secrete pro-fibrogenic mediators, including TGF-β1, which promote the progression of liver fibrosis.157 In brief, the recruitment and mobilization of immune cells, the accumulation of inflammation, and the activation of hepatic stellate cells and hepatocytes contributes to the development of liver fibrosis and the aging process (Fig. 3).

Other organsSkin

During the aging process, the skin accumulates senescent cells that, despite their inability to divide, remain metabolically active. These senescent cells exhibit an altered secretome known as SASP, which significantly disrupts the skin microenvironment.158 For instance, senescent dermal fibroblasts secrete a higher amount of extracellular vesicles (EV) compared to their non-senescent counterparts. This increased EV secretion hampers the normal differentiation of keratin-forming cells and compromises the skin’s barrier function. In addition, it triggers the elevated production of the pro-inflammatory cytokine IL-6.159

Furthermore, skin aging can occur due to age-related factors or exposure to environmental stressors like ultraviolet radiation.

The process of skin aging can also have systemic effects on the overall aging process of the body, primarily through the activation of SASP.160 The presence of p16-positive cells in the skin, which is a marker of cellular senescence, has been found to be associated with markers of CD4+ T-cell senescence and biological age.161,162 Notably, the microbiome of skin has been found to predict a person’s actual age accurately.160,163 While the numbers of CD4 T cells remain consistent with age, the levels of CD8 T cells are higher in older skin compared to younger skin.164 The ratio of cutaneous CD4 T cells to CD8 T cells is greater in aged individuals, but the number of CD4 T cells is not elevated in aged skin.165 Moreover, aged skin exhibits increased numbers of regulatory T cells (Tregs)166 and elevated expression‎ of the immunosuppressive receptor PD-1,165,167 which may contribute to weakened adaptive immunity. These changes could be a response to an inflammatory state exacerbated by impaired epidermal barrier function or fibroblast senescence, further promoting an inflammatory microenvironment (Fig. 3).

Lung

The aging process brings about notable transformations in the structure and function of the lungs, including a decline in mucociliary clearance and heightened vulnerability to pulmonary infections.168,169 These alterations contribute to the onset and progression of various lung diseases like idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).169 Several cell types within the lungs undergo modifications during aging, including respiratory epithelial cells, lung progenitor cells, lung immune cells, and lung interstitial cells.169 Among these cell types, alveolar epithelial type II cells (AT2) are a significant population responsible for regenerating the alveolar parenchyma. However, as these cells age, the airway epithelium experiences quantitative and qualitative defects. The number of basal and spherical cells decreases, while the count of AT2 cells remains unchanged but exhibits impairments in self-renewal and differentiation capacity.170,171,172 Moreover, age-related changes in the lung environment, such as alterations in extracellular matrix (ECM) components, tissue and circulating cytokines, SASP, and structural abnormalities, can lead to abnormal intercellular communication mechanisms. This is evident through distorted interactions with microbial pathogens and a shift in innate and adaptive immunity towards increased inflammation, disrupted adaptive immune responses, and impaired immune surveillance (Fig. 3).173

The increased susceptibility of elderly individuals to lung diseases can be ascribed to age-related changes in immunity and anti-infection responses. The phagocytic capacity of pulmonary and alveolar macrophages diminishes with age, impairing the clearance of pathogens from the lungs.51,174,175 Dendritic cells, neutrophils, and NK cells also experience age-related alterations in their numbers and functionality.169 In addition, the aging process is linked with a decrease in CD4, and CD8 T cell populations. The decline in naive T cell numbers is accompanied by an increase in the number of memory T cells. The CD4 to CD8 lymphocyte ratio in bronchoalveolar lavage fluid tends to rise with age, indicating a reduction in the pool of naive T cells available for conversion into memory cells in response to new antigens. Furthermore, aging is associated with reduced CD4 and CD8 T cell responses, diminished TCR repertoire diversity, impaired Th cell differentiation, and reduced Th cell activity.176 These age-related changes in T cell number and function can compromise influenza vaccination immunity and cytotoxicity against the virus. The adaptive immune response to antigens also declines with age, which explains why older individuals are more susceptible to environmental stimuli. Notably, immune cell disorganization associated with aging may contribute to the heightened severity of COVID-19 and chronic obstructive pulmonary disease (COPD) in the elderly.169,177

To recapitulate, age-related changes in T cell-mediated adaptive immune responses enhance vulnerability to infectious agents and result in severe diseases.

Gut

Age-related perturbations in the gut microbiome have emerged as crucial factors contributing to age-related pathological conditions, including chronic inflammation,178 neurodegeneration,179 cognitive decline,180 and type 1 and type 2 diabetes.181 The gut microbiota comprises probiotic, commensal, and pathogenic bacteria, and the imbalance between intestinal flora and aging mutually influences and exacerbates each other. Older adults (>65 years) exhibit reduced microbiota diversity compared to adults, along with greater inter-individual variation in microbiota composition.182 This is characterized by diminished populations of beneficial bacteria such as Bifidobacterium, Bacillus, E. coli, Clostridium XIV, Blautia coccoides-Eubacterium rectal, and Bacteroidetes, and increased presence of Enterobacteriaceae.183 However, it’s important to note that data regarding age-related changes in microbiome composition can vary among populations.

Age-related alterations in the intestinal microbiota, particularly due to prolonged immune system stimulation, can contribute to the accumulation of inflammation and a decline in immune system function known as immunosenescence.184 Interestingly, two previous studies have indicated that changes in the relative abundance of gut microbiota are more likely to be influenced by inflammation rather than age, with TNF playing a significant role.185,186 This suggests that the changes in gut microbiota are more closely related with inflammatory processes rather than solely being a consequence of aging (Fig. 3).187,188

Mechanisms of inflammaging

Consensus features of inflammaging

While the precise interpretation of senescent cell markers remains incomplete and requires further investigation, there is a consensus regarding certain essential characteristics of senescent cells, primarily focusing on the SASP (Table 1). The SASP, considered to be molecular inflammation, is a universal, dynamic, and complex phenomenon arising with cellular senescence. It is the phenomenon of senescent cells secreting pro-inflammatory cytokines.189 The SASP possesses the capacity to perpetuate senescence itself or influence the surrounding tissue microenvironment, consequently affecting the entire organism. Classic SASP factors contain pro-inflammatory and immune-modulatory cytokines, chemokines, proteases, and growth factors (Table 1).190,191,192,193 According to its complex composition, the SASP has been implicated in the majority of the nonautonomous effects observed in senescent cells, including inflammation, immune evasion, tumor promotion, senescence reinforcement, paracrine senescence, and so on.194 Recent analysis has identified a set of shared components within the SASP that are consistent across various inducers of senescence and different cell types. Interestingly, some of these components overlap with aging markers observed in human plasma, including serine protease inhibitors, stanniocalcin 1, and growth differentiation factor 15.190 Furthermore, dysfunctional mitochondria,195 persistent DNA damage response,196 CCAAT/enhancer-binding protein β (C/EBPβ) and NF-κB,197 mTOR, and other factors are involved in regulating SASP.194

In addition, SASP encompasses additional characteristics such as lipofuscin accumulation within lysosomes, increased cytoplasmic DNA, activation of anti-apoptotic pathways, and alterations in the nucleus, including the loss of Lamin B1, telomere shortening, senescence-associated heterogeneous chromatin aggregation, and the presence of telomerase-associated foci.198 At the transcriptional level, p16 and p21 are the most commonly used markers to identify senescent cells. These features and markers have been extensively employed to detect senescent cells in various tissues, both in the context of individual senescence and other pathological conditions.199

염증성 노화 메커니즘

염증성 노화의 공통적 특징

노화 세포 표지자의 정확한 해석은 아직 불완전하며 추가 연구가 필요하지만, 노화 세포의 필수적 특성 중 일부에 대한 공감대가 형성되어 있으며, 이는 주로 SASP(Table 1)에 초점을 두고 있습니다.

SASP는 분자적 염증으로 간주되며, 세포 노화와 함께 발생하는 보편적, 동적, 복잡한 현상입니다. 이는 노화 세포가 염증성 사이토카인을 분비하는 현상입니다.189 SASP는 노화 자체를 지속시키거나 주변 조직 미세환경에 영향을 미쳐 결국 전체 유기체에 영향을 미칠 수 있는 능력을 갖추고 있습니다. 전통적인 SASP 인자에는 염증성 및 면역 조절 사이토카인, 케모카인, 프로테아제, 성장 인자가 포함됩니다(표 1). 190,191,192,193

복잡한 구성에 따라 SASP는 노화 세포에서 관찰되는 대부분의 비자율적 효과, 즉 염증, 면역 회피, 종양 촉진, 노화 강화, 파라크린 노화 등에 관여하는 것으로 밝혀졌습니다.194 최근 분석은 노화 유도 인자와 다양한 세포 유형에서 일관되게 관찰되는 SASP 내 공통 구성 요소를 식별했습니다. 흥미롭게도, 이러한 구성 요소 중 일부는 인간 혈장에서 관찰된 노화 표지자와 중복됩니다.

예를 들어 세린 프로테아제 억제제, 스탄니오칼신 1, 성장 분화 인자 15 등이 있습니다.190

또한, 기능 장애를 보이는 미토콘드리아,195 지속적 DNA 손상 반응,196 CCAAT/강화 인자 결합 단백질 β (C/EBPβ) 및 NF-κB,197 mTOR 등 다른 요인들도 SASP 조절에 관여합니다.194

또한 SASP는

리소좀 내 리포푸신 축적,

세포질 내 DNA 증가,

항아포토시스 경로 활성화,

핵 내 변화(라민 B1 상실, 텔로미어 단축, 노화 관련 이질적 염색질 집적, 텔로머레이스 관련 초점 존재 등)와 같은

추가적인 특성을 포함합니다. 198

전사 수준에서 p16과 p21은

노화 세포를 식별하는 가장 일반적으로 사용되는 마커입니다.

이러한 특징과 마커는 개별 노화 및 기타 병리적 조건에서

다양한 조직의 노화 세포를 탐지하는 데 광범위하게 활용되었습니다.199

Triggers of inflammaging

Inflammaging develops from cold-inflammaging with a less than 2-fold increase of pro-inflammatory mediators in plasma, compared to healthy adults.200 This slightly altered level is a positive response for maintaining homeostatic stability. However, during aging, the homeostasis imbalance arises and progresses, leading to increased cytokine response (2- to 4-fold increase) mediated by the chronic activated innate immune system. The transition is highly influenced by several vital triggers, including cellular senescence with the secretion of SASP, which have been already mentioned above, dysbiosis caused by microbiome and their metabolites, and endogenous molecular garbage caused by abnormal cell death.

Oxidative stress

Oxidative stress leads to oxidative damage to biomolecules (especially DNA),201 causing endogenous damage-associated molecular patterns (DAMPs) production and cytokine release in the organism.202,203 Cytokines activate downstream signaling pathways of pattern recognition receptors,203 causing systemic chronic inflammatory responses in the body.204 Consequently, oxidative stress is recognized as a concurrent occurrence within the inflammatory process, amplifying the inflammatory response through oxidation. At the same time, inflammation promotes oxidation through inflammatory mediators.205,206 Based on the close relationship among oxidative stress, inflammation, and aging, Dela Fuente et al. proposed the theory of aging by oxidation-inflammation (oxi-inflamm-aging)207,208 and concluded that oxidative stress leads to inflammatory aging. Oxidative stress has been ensured as a crucial factor for cellular senescence through shortening telomere and causing DNA double-strand breaks.209,210 Moreover, infections,211 environmental pollution,212,213 and adverse lifestyle habits214 can increase oxidative stress.

염증성 노화의 유발 요인

염증성 노화는 건강한 성인에 비해 혈장 내 염증 유발 매개체의 2배 미만의 증가를 동반한 냉각성 염증성 노화에서 발생합니다.200 이 약간 변화된 수준은 항상성 안정성을 유지하기 위한 긍정적인 반응입니다. 그러나 노화 과정에서 항상성 불균형이 발생하고 진행되면서 만성적으로 활성화된 선천성 면역 체계에 의해 매개되는 사이토킨 반응이 증가합니다(2~4배 증가). 이 전환은 세포 노화(SASP 분비 포함, 위에서 이미 언급됨), 미생물군집과 그 대사산물에 의한 dysbiosis, 비정상적 세포 사멸로 인한 내인성 분자 쓰레기 등 여러 중요한 유발 요인의 영향을 크게 받습니다.

산화 스트레스

산화 스트레스는 생체 분자(특히 DNA)에 산화 손상을 일으키며,201 이는 내인성 손상 관련 분자 패턴(DAMPs)의 생성 및 세포 내 사이토킨 방출을 유발합니다.202,203 사이토킨은 패턴 인식 수용체의 하류 신호 전달 경로를 활성화시켜,203 신체 내 전신성 만성 염증 반응을 유발합니다.204 따라서 산화 스트레스는 염증 과정 내 동시 발생 현상으로 인식되며, 산화를 통해 염증 반응을 증폭시킵니다. 동시에 염증은 염증 매개체를 통해 산화를 촉진합니다.205,206 산화 스트레스, 염증, 노화 사이의 밀접한 관계에 기반해 Dela Fuente 등(207)은 산화-염증 노화(oxi-inflamm-aging) 이론을 제안했으며, 산화 스트레스가 염증성 노화를 유발한다고 결론지었습니다. 산화 스트레스는 텔로미어 단축과 DNA 이중 가닥 파열을 통해 세포 노화의 중요한 요인으로 확인되었습니다.209,210 또한 감염,211 환경 오염,212,213 및 불건강한 생활 습관214는 산화 스트레스를 증가시킬 수 있습니다.

Microbiome

Recently, there has been an increasing focus on studying age-specific changes in the intestinal microbiome and its role in regulating inflammation. A healthy gut microbiome is essential for body metabolism, infection resistance, inflammation regulation, prevention of autoimmunity and cancer, and brain-gut axis regulation.215 However, with age, there is a decrease in beneficial microorganisms216,217 and an accumulation of potentially pro-inflammatory microorganisms in the gut,218 leading to a change in microbial composition and a decrease in microbial diversity. Moreover, this phenomenon exists simultaneously in species such as Drosophila,219 fish,220 mice,221 rats,222 and humans.223 The detailed gut microbiota changes with aging have been collected and discussed by Du et al.224 Recent studies have revealed that the transplantation of fecal matter from young donors into the gastrointestinal tract of middle-aged fish can effectively prolong lifespan and delay the onset of behavioral decline,220 and that fecal transplantation from young mice slows HSC senescence in the bone marrow.225 Lachnospiraceae and tryptophan-associated metabolites have emerged as key players in important biological processes, but the exact mechanism and involvement of other factors are not yet clear. Nonetheless, it is evident that the senescence-related remodeling of microorganisms mediates the accumulation of chronic inflammation, which is highly correlated with their metabolites and their induced immune responses.

미생물군집

최근에는 장 미생물군집의 연령별 변화와 염증 조절에 미치는 역할에 대한 연구가 증가하고 있습니다. 건강한 장 미생물군은 신체 대사, 감염 저항성, 염증 조절, 자가면역 질환 및 암 예방, 뇌-장 축 조절에 필수적입니다.215 그러나 연령이 증가함에 따라 유익한 미생물의 감소216,217 및 장 내 잠재적으로 염증 유발성 미생물의 축적이 발생하며,218 이는 미생물 구성의 변화와 미생물 다양성의 감소로 이어집니다. 또한 이 현상은 Drosophilia,219 어류,220 쥐,221 쥐,222 인간 등 다양한 종에서 동시에 관찰됩니다. 223 노화에 따른 장 미생물군 변화의 세부 사항은 Du 등224에 의해 수집되고 논의되었습니다. 최근 연구에서는 젊은 기증자의 분변을 중년 어류의 소화관에 이식하는 것이 수명을 연장하고 행동 저하의 발현을 지연시키는 데 효과적임을 보여주었으며,220 젊은 쥐의 분변 이식이 골수 내 HSC 노화를 늦추는 것으로 나타났습니다. 225 Lachnospiraceae와 트립토판 관련 대사산물은 중요한 생물학적 과정의 핵심 요소로 부상했지만, 정확한 메커니즘과 다른 요인의 관여는 아직 명확하지 않습니다. 그럼에도 불구하고, 노화 관련 미생물의 재편성이 만성 염증의 축적을 매개하며, 이는 그들의 대사산물과 유발된 면역 반응과 밀접하게 연관되어 있다는 것은 분명합니다.

Inflammatory cell death

Eukaryotic cells possess the ability to activate various self-destructive mechanisms, but the type of cell death can be classified as either inflammatory or non-inflammatory. In normal tissues, cell death serves as a highly conserved process that promotes a stable cell population through the elimination of surplus, impaired, or aged cells. Consequently, the human body generates over 150 billion deceased cells on a daily basis.226 A newly developed conception, garb-aging, reveals that the production of inflammatory cell death modalities, endogenous molecular garbage (e.g., mitochondrial RNA, misplaced molecules, and cell debris), is a causal inflammatory stimuli that can accelerate inflammaging.227,228 Certain cytokines, such as IL-1β and IL-6, have clearly emerged as key to promoting inflammaging.83,229,230,231,232 Moreover, inflammatory death of internal cells due to exogenous factors such as infection also promotes the progression of inflammaging.17,233 During aging, the imbalance between the increased production and decreased disposal via autophagy, mitophagy, and proteasome, stimulus the innate immune system and thereby triggers the body from a pre-inflammatory state towards a pro-inflammatory state.234

Necrosis

As the body ages, tissues and cells gradually experience damage, leading to a decline in their abilities and functions. Aging cells may be more susceptible to damage from external stimuli, increasing the risk of necrosis. In addition, certain age-related diseases such as cardiovascular diseases and neurodegenerative disorders may be accompanied by cellular necrosis.

Necrosis is traditionally considered an unprogrammed and unregulated form of cell death that occurs due to overwhelming external stimuli.235 It is characterized by cellular swelling, loss of membrane integrity, release of intracellular contents (DAMPs and pathogen-associated molecular pattern, PAMPs) into the extracellular environment, an increase in intracellular calcium concentration, and the generation of ROS. These events ultimately lead to irreversible cellular damage. DAMPs, such as HMGB1, uric acid, nucleosomes, and members of the heat shock protein family (HSP 70, HSP 60, and GP96), can directly or indirectly activate and recruit immune cells, thereby triggering inflammation or immunosuppression.236 It is important to note that these factors can be released during the entire process of cell death, even when cells are still metabolically active. Consequently, cells in the process of dying may contribute to carcinogenesis even before the appearance of obvious necrotic changes (Fig. 4).236

염증성 세포 사멸

진핵세포는 다양한 자살 메커니즘을 활성화할 수 있지만, 세포 사멸의 유형은 염증성 또는 비염증성으로 분류됩니다. 정상 조직에서 세포 사멸은 과잉, 손상된, 또는 노화된 세포를 제거함으로써 안정적인 세포 집단을 유지하는 고도로 보존된 과정입니다. 따라서 인간 몸은 매일 1500억 개 이상의 사멸한 세포를 생성합니다. 226 새롭게 제안된 개념인 '가르-에이징(garb-aging)'은 염증성 세포 사멸 모드와 내인성 분자 쓰레기(예: 미토콘드리아 RNA, 위치가 잘못된 분자, 세포 잔여물)의 생산이 염증성 노화(inflammaging)를 가속화하는 원인적 염증 자극제임을 밝혔습니다.227,228 IL-1β와 IL-6와 같은 특정 사이토카인은 염증성 노화를 촉진하는 핵심 요인으로 명확히 부상했습니다. 83,229,230,231,232 또한 감염과 같은 외인성 요인에 의한 내부 세포의 염증성 사멸도 염증성 노화의 진행을 촉진합니다.17,233 노화 과정에서 자가포식, 미토포식, 프로테아좀을 통한 생성 증가와 제거 감소의 불균형이 선천적 면역 체계를 자극하여 신체를 염증 전 상태에서 염증 촉진 상태로 전환시킵니다.234

괴사

신체가 노화함에 따라 조직과 세포는 점차 손상을 입어 기능과 능력이 감소합니다. 노화된 세포는 외부 자극에 대한 손상 위험이 증가하여 괴사의 위험이 높아집니다. 또한 심혈관 질환 및 신경퇴행성 질환과 같은 특정 노화 관련 질환은 세포 괴사와 동반될 수 있습니다.

괴사는 전통적으로 외부 자극에 의해 유발되는 계획되지 않고 조절되지 않은 세포 사멸로 간주됩니다.235 이는 세포 부종, 세포막의 무결성 상실, 세포 내 내용물(DAMPs 및 병원체 관련 분자 패턴, PAMPs)의 세포 외 환경으로의 방출, 세포 내 칼슘 농도 증가, 활성 산소 종(ROS)의 생성으로 특징지어집니다. 이러한 사건은 결국 세포의 회복 불가능한 손상으로 이어집니다. DAMPs는 HMGB1, 요산, 뉴클레오좀, 열 충격 단백질 가족(HSP 70, HSP 60, GP96)의 구성원 등이며, 면역 세포를 직접 또는 간접적으로 활성화하고 모집하여 염증 또는 면역 억제를 유발할 수 있습니다.236 이러한 요소는 세포가 여전히 대사적으로 활성 상태일 때조차 세포 사멸 과정 전반에 걸쳐 방출될 수 있다는 점을 주목해야 합니다. 따라서, 세포 사멸 과정에 있는 세포는 명백한 괴사 변화가 나타나기 전에 암 발생에 기여할 수 있습니다(그림 4).236

Fig. 4

Schematic diagram of six inflammatory cell death molecular patterns.

The source of inflammation comes from cell death in addition to the release of SASP from senescent cells. Both immune response-mediated and damage signaling-mediated cell death promote inflammation to some extent. Various modes of cell death (in addition to apoptosis) release large amounts of inflammatory factors

Full size image

Necroptosis

Necroptosis (previously named programmed necrosis) is a regulated form of inflammatory necrosis that occurs when apoptosis (the programmed cell death process) fails. Its identification questioned the conventional notion that necrosis is exclusively an inert process induced by overwhelming stress. Necroptosis is distinguished by the early disruption of plasma membrane integrity, release of intracellular contents, and enlargement of organelles. Apoptosis is generally regarded as non-immunogenic since the regulated dismantling of apoptotic cells restricts the liberation of DAMPs. However, necroptosis triggers inflammation through the massive release of DAMPs from the disintegrating cell.237

The contribution of DAMPs from dying cells in the RIPK1-RIPK3 inflammasome-dependent pathway of cytokine production varies. Upregulation of RIPK3 has been observed in hepatocytes, suggesting that RIPK3-dependent necroptosis may play a role in inflammation and hepatocyte death. Immunostaining with antibodies recognizing phosphorylated mixed lineage kinase domain-like protein (MLKL) serves as a specific marker of necroptosis.238,239 In addition, immunostaining using antibodies that target phosphorylated MLKL has been identified as a specific marker for necroptosis.240

Focus on liver, its aging has been linked to an increase in necroptosis, and this process has been found to contribute to chronic liver inflammation, which in turn appears to be involved in the development of liver fibrosis.241 On the other hand, in the livers of old mice (specifically, those aged 18 months and older), there was a significant upregulation of phosphorylated MLKL and MLKL oligomers, which are markers associated with necroptosis. In addition, the phosphorylation of RIPK3 and RIPK1, two key proteins involved in necroptosis signaling, was also significantly increased in the livers of old mice compared to young mice. In comparison to young mice, hepatocytes and liver macrophages from old mice had higher levels of necroptosis markers and higher expression‎ of pro-inflammatory cytokines M1 macrophage markers, pro-inflammatory cytokines (TNF-α, IL-1, and IL-6), and fibrosis markers. In the livers of old mice, short-term treatment with the necroptosis inhibitor necrostatin-1s (Nec-1s) reduced necroptosis, M1 macrophage markers, cellular senescence, fibrosis, and pro-inflammatory cytokines.241 Importantly, nerve injury-induced protein 1 (Ninjurin1/Ninj 1) plays a crucial role in facilitating the ultimate breach of the plasma membrane that takes place in necroptosis, pyroptosis, and secondary necrosis. Secondary necrosis refers to the phenomenon where cells undergoing apoptosis fail to be engulfed by adjacent phagocytes (Fig. 4).242 These findings suggest an age-associated dysregulation of necroptosis signaling, indicating a potential role for necroptosis in aging and related pathologies.

Pyroptosis

As the body ages, tissues and cells gradually experience damage, leading to a decline in their abilities and functions. Similar to other forms of inflammatory cell death, aging cells may also be more susceptible to damage from external stimuli that can trigger pyroptosis, increasing the risk of pyroptosis occurrence. In addition, age-related diseases such as neurodegenerative disorders and cardiovascular diseases may be accompanied by cellular pyroptosis. Specifically, pyroptosis may play a specific role in aging. Inflammation and cell death have important regulatory roles in aging, and pyroptosis, as an inflammatory form of cell death, may contribute to the inflammatory response and cellular dysregulation in the aging process.243 Moreover, pyroptosis may be involved in the development and progression of age-related diseases.

In the non-classical pathway, human-derived caspase-4, 5, and murine-derived caspase-11 can be activated upon direct contact with bacterial lipopolysaccharide (LPS). LPS cleaves gasdermin D (GSDMD), which indirectly activates caspase-1, leading to pyroptosis. Alternatively, caspase-1 can be recruited and activated by inflammatory vesicles that detect danger signals. Activated caspase-1 cleaves and activates inflammatory factors, which in turn cleave the N-terminal sequence of GSDMD. This results in the binding of GSDMD to the membrane and the generation of membrane pores, ultimately leading to pyroptosis (Fig. 4). Evidence of pyroptosis, coincided with elevated levels of IL-1 and IL-18, and inflammasome activation, has been illustrated in various conditions such as atherosclerosis, neurodegenerative diseases, cancer, and chimeric antigen receptor (CAR)-T therapy.244,245,246,247

Ferroptosis

As the body ages, changes in iron levels and iron metabolism may occur. The accumulation of iron in cells during the aging process may be associated with the development of age-related diseases such as neurodegenerative diseases248 and cardiovascular diseases.249 This iron accumulation can lead to increased generation of ROS within cells, thereby triggering iron-dependent cell death known as ferroptosis. The main drivers of ferroptosis are the inactivation of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and the induction of ROS, particularly lipid ROS. GPX4 plays a cytoprotective role by reducing cellular lipid hydroperoxide levels, which are associated with inflammation. In cancer cells, certain inflammatory cytokines such as TNF, PGE2, IL-1, and IL-6 have been shown to directly affect GPX4 levels and activity. Treatment with TNF, for example, downregulates GPX4, leading to ferroptosis.

Ferroptosis is an inflammatory form of cell death that is distinct from apoptosis. It is characterized by iron-dependent lipid peroxidation and can contribute to various pathological processes, including neurodegenerative diseases, inflammatory diseases, autoimmune diseases, and cancer. The inactivation of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and the induction of ROS, particularly lipid ROS, are the main causes of iron death. GPX4 has been shown to have a cytoprotective effect by lowering the levels of cellular lipid hydroperoxides.250 Several pro-inflammatory cytokines, including TNF, PGE2, IL-1, and IL-6, have been demonstrated to exert a direct influence on the levels and function of GPX4 within cancer cells;251 for example, TNF treatment causes GPX4 downregulation that can lead to ferroptosis.252 High mobility group box 1 (HMGB1), a DAMP, has been implicated in inflammation and its pathogenesis.253,254 In the context of ferroptosis, inhibiting HMGB1 release has been shown to limit the inflammatory response during cell death. Anti-HMGB1 antibodies have demonstrated their ability to reduce the inflammatory response in macrophages induced by ferroptotic cells.252 Ferroptosis inhibitors have shown promise in the treatment of certain diseases due to their anti-inflammatory properties. In an oxalate-induced mouse model of AKI, evidence of inflammation was observed, and the ferroptosis inhibitor Ferrostatin-1 successfully inhibited neutrophil infiltration and the expression‎ of pro-inflammatory cytokines such as CXCL-2 and IL-6.255,256 Conversely, the ferroptosis inducer RSL-3 significantly increased the protein levels of pro-inflammatory cytokines like TNF, IL-1, and IL-6, exacerbating hepatosteatosis, lobular inflammation, and apoptosis (Fig. 4).257 The results indicate a possible interplay between ferroptosis and inflammation.

In addition, certain biological processes and molecular mechanisms associated with aging may be related to ferroptosis. During the aging process, alterations in cellular function and metabolism can increase the sensitivity of cells to external stimuli, including sensitivity to ferroptosis. Recent studies have reported the involvement of ferroptosis as a mechanism that promotes skeletal muscle aging.258 With skeletal muscle aging, there is a decreased expression‎ of Tfr1 and an increased expression‎ of Slc39a14, which is enriched on the cell membrane surface of aging mouse skeletal muscle cells. This increase in Slc39a14 leads to enhanced non-transferrin-bound iron uptake, resulting in the accumulation of free iron ions within skeletal muscle and the occurrence of ferroptosis.258

Lastly, the interaction between ferroptosis and aging may be bidirectional. On one hand, ferroptosis may play a role in the development of certain age-related diseases, accelerating tissue and cellular aging processes. On the other hand, the cellular functional and metabolic changes that occur during the aging process may increase the sensitivity of cells to ferroptosis, further promoting disease progression.

NETosis

NETosis is a special form of cell death closely associated with inflammation and immune response. It is a cell death program executed by neutrophils and is characterized by the release of net-like structures (neutrophil extracellular traps/ NETs). These structures are composed of DNA, histones, and microbial toxins, among other components, and serve the purpose of capturing and killing microorganisms.228 NETosis plays a significant role in various pathologies, including COVID-19, Kawasaki syndrome, and rheumatoid arthritis (RA). Excessive NETosis has been implicated in the development of cytokine storms and thrombosis.259 In COVID-19, NETosis can be caused by virus-infected epithelial and endothelial cells, thereby activating inflammatory cytokines and platelets. Excessive NETosis, accompanied by increased circulating free DNA and Neutrophil Extracellular (NE)-DNA complexes, is also found in acute Kawasaki syndrome, a vasculitis occurring in children.260

In RA, the disease pathology is characterized by the accumulation of DNA-MPO complexes and the presence of antibodies targeting guanylated histones (NETosis markers).261,262 In myocarditis, NETosis probably promotes PMN trafficking via MK and substantially contributes to cardiac inflammation.263 In systemic lupus erythematosus, NETosis activates the plasmacytoid and induces the production of IFN-α and ROS, which contribute the following further inflammation.264,265,266,267 On the other hand, the anti-microbial effects of NETosis have been observed to slow down the spread of pathogens in infected lesions. NETs in staphylococcal skin infections inhibit the penetration of pathogens into the bloodstream.268 Knockout of the PAD4 gene in mice prevents NET formation and leads to more severe necrotizing fasciitis caused by streptococcus pyogenes. In summary, NETosis could cause inflammation or conversely slow the onset of age-related diseases (Fig. 4).

The ability of neutrophils to undergo NETosis may be affected by aging.269 Senescent neutrophils exhibit several distinct characteristics during NETosis, including a reduced capacity to release NETs, instability in the quality of formed NETs, and decreased activity of DNA degrading enzymes (DNases) within NETs. These age-related changes can result in impaired functionality of aging neutrophils, leading to deficiencies in their ability to effectively combat microbial infections and regulate inflammatory responses.

Moreover, aging is often accompanied by a phenomenon called inflammaging, which refers to a chronic low-grade inflammatory state. Inflammaging can further contribute to the occurrence of NETosis. This persistent inflammatory condition enhances the activity of inflammatory cells, including neutrophils, thereby increasing the likelihood of NETosis. A previous study found that aged mice exhibited an increased propensity for NETosis compared to younger mice. This heightened NETosis activity was associated with the activation of peptidylarginine deiminase 4 (PAD4), an enzyme involved in the formation of NETs. The excessive formation of NETs, in turn, was implicated in the development of age-related organ fibrosis.270

In conclusion, the process of aging can adversely affect the ability of neutrophils to undergo NETosis. Senescent neutrophils may experience limitations in NET release, compromised stability of formed NETs, and reduced DNase activity within NETs. In addition, the presence of inflammaging, the age-associated inflammatory state, can intensify the occurrence of NETosis by stimulating inflammatory cell activity. However, further research is necessary to fully comprehend the intricate mechanisms and interactions between aging and NETosis.

PANoptosis

PANoptosis, is a united modality of inflammatory programmed cell death, accompanied by markers of apoptosis, necrosis, and pyroptosis pathways.271,272,273,274,275 Influenza A virus was first discovered to cause PANoptosis, followed by many other infections, of bacterial, fungal, and viral origin.275

PANoptosis is involved in the occurrence of cytokine storms (CS) characterized by excessive cytokine production.276 The combination of TNF-α and IFN-γ activates the JAK/STAT1/IRF1 signaling pathway, leading to the production of nitric oxide (NO). This NO release triggers PANoptosis through the involvement of GSDME (pyroptotic), CASP8/3/7 (apoptotic), and pMLKL (necroptotic) pathways. In vivo, blocking CS by giving mice anti-TNF-α and anti-IFN-γ antibodies prevents death from SARS-CoV-2 infection, hemophagocytic lymph histiocytosis, and LPS shock (sepsis).276 This highlights the critical role of TNF-α and IFN-γ released from PANoptosis in driving cytokine storms during infections and inflammatory conditions.275 Cytokines or PAMPs trigger the assembly of a multiprotein complex called the PANoptosome. This complex includes various molecules necessary for the activation of downstream programmed cell death (PCD) effectors such as GSDMD, GSDME, CASP3/7, and MLKL (Fig. 4). No direct evidence yet links PANoptosis to aging. However, aging can affect cell responses to inflammation and cell death. Further research is needed to explore the potential connection between aging and PANoptosis, shedding light on its impact on immune and cell death mechanisms.

In summary, DAMPs from senescent, damaged, and dying cells trigger various cell death modalities, including necrosis, pyroptosis, necroptosis, PANoptosis, NETosis, and ferroptosis (Fig. 4). DAMPs bind to specific receptors, initiating inflammation and orchestrating a coordinated response involving immune cells. This response includes the recruitment of neutrophils and monocytes, which play crucial roles in tissue repair and healing processes. When leukocytes fail to clear immunostimulatory molecules, inflammation persists, which further causes cancer and aging. Endogenous DAMPs can activate PRRs and non-PRR transmembrane proteins, resulting in massive inflammation, cellular senescence, diseases of the organs, and aging.277,278,279 The shift of understanding in aging mechanisms, from the cellular and organ level to the molecular level, aid in identifying novel targets for anti-inflammatory therapies and effective anti-aging interventions.

Classical models to study aging

Aging model systems can simulate human physiological and pathological processes to reveal aging mechanisms and guide anti-aging research. To date, aging models consist of in vitro models (e.g., physical, chemical, and biological induced models) and in vivo models (e.g., animal models, premature aging models, and centenarian).

In vitro models

Here, we describe the main in vitro models of senescence used in research, classified according to different stimuli: replicative senescence (RS), oncogene-induced senescence (OIS), and chemotherapy-induced senescence (CIS).

Replicative senescence (RS) models

Replicative senescence is closely associated with the shortening of telomeres. In the laboratory aging of human diploid fibroblasts (HDFs), as the cells undergo a certain number of population doublings, telomeres become shorter, leading to cell cycle arrest, reduced cell saturation density, and increased cell surface and volume.280 Hydrogen peroxide is commonly used to induce stress-induced premature senescence (SIPS), which shares similarities with replicative senescence. When young HDFs are exposed to prolonged low doses of hydrogen peroxide, they enter irreversible G1 cell cycle arrest and exhibit senescence-associated beta-galactosidase activity. These cellular senescence markers are accompanied by increased expression‎ of p21, gadd45, and enhanced p53 binding activity.281 In addition, DNA repair capability decreases, and telomere shortening accelerates. Hydrogen peroxide-induced senescence also triggers inflammation, characterized by the upregulation of pro-inflammatory cytokines such as IL-6, TNF-α, and MCP-1.282,283

Oncogene-induced senescence (OIS)

Oncogene-induced senescence (OIS) is observed following the activation of various oncogenes such as B-RAFV600E or H-RAS G12V, as well as the loss of tumor suppressor proteins like PTEN or NF-1, in different cell types.284 OIS is often associated with DNA replication stress and hyper-replication. It is characterized by the upregulation of CDK inhibitors, including p15INK4B, p16INK4A, p21CIP1, and an increased senescence-associated β-galactosidase (SA-β-Gal) activity.285,286

Kuilman et al. discovered that OIS is specifically associated with the induction of an inflammatory gene expression‎ profile, which includes the expression‎ of various genes such as the pleiotropic cytokines IL-6, IL-1α, IL-1β, and IL-8. In addition, the transcription factor C/EBPbeta collaborates with IL-6 to enhance initiation of the pro-inflammatory cascade, as demonstrated in cells carrying B-RAFV600E and H-RAS G12V mutations.287

Chemotherapy-induced senescence (CIS)

Chemotherapy-induced cellular senescence is a commonly used cellular model. Drugs like doxorubicin can induce cells to enter a senescent state.288 In this model, cells treated with doxorubicin display characteristic features of senescence. For instance, the expression‎ of 4-HNE and GPX4 increases, while SIRT1 expression‎ decreases. Furthermore, these senescent cells exhibit elevated levels of pro-inflammatory cytokines like IL-6, IL-17, and TNF-α, along with reduced levels of the anti-inflammatory cytokine IL-4, indicating the presence of inflammation.289 Similarly, treatment of melanoma cells with Palbociclib leads to cell cycle arrest at the G0/G1 phase, accompanied by SA-βgal and SASP that includes factors such as IL-6, IL-8, and CXCL1.290 In addition, doxorubicin-induced senescence in H9c2 myocardial cells results in increased expression‎ of 4-HNE and GPX4, decreased SIRT1 expression‎, and heightened levels of pro-inflammatory cytokines (IL-6, IL-17, and TNF-α), while the anti-inflammatory cytokine IL-4 is reduced.291,292,293 Furthermore, primary human astrocytes exposed to X-rays exhibit increased expression‎ of senescence-associated proteins (p16INK4a and Hp1γ) and cytokines associated with SASP, such as IL-1β and IL-6.294,295,296 Further details of other in vitro models are shown in Table 2.

Table 2 Multiple models to study aging

Table 2 Multiple models to study aging

From: Inflammation and aging: signaling pathways and intervention therapies

Model typeModel nameDescription

In vitro models
Replicative senescence (RS)	Replicative senescence model375,376	Reduced saturation density, heightened cell surface area and volume, cell cycle arrest, shortened telomeres, and an increased occurrence of SA-β-gal positive staining
Chemotherapy-induced senescence (CIS)	hydroxyurea induced model377	Increased ROS and SA-β-gal positive staining and decreased cell proliferation
	Aβ1-42 oligomers model (AD model)378,379	Increased ROS and SA-β-gal positive staining, PAI-1 and p21 mRNA levels, and decreased SIRT1
	D-galactose model299	Increased ROS, SA-β-gal positive staining, inflammation level, P16, P21 and P53 genes, and decreased of NRF2 and HO-1
	Doxorubicin (a DNA topoisomerases inhibitors)380,381	Cell cycle arrest, DNA damage, telomere shortening, increased expression‎ of p16lnk4a
	Palbociclib treated (a CDK4/CDK6 inhibitor)382	G0/G1 arrest, growth arrest, reduced Rb expression‎, increased SA-β-gal positive staining, and IL-6, IL-8, CXCL1 secretion
Stress induced premature senescence (SIPS)	X-ray induced model383,384	Irreversible G1 cell cycle arrest, DNA damage, increased SA-β-gal positive staining, IL-1β, IL-6, IL-8 and other SASP cytokines
	UVB induced model385	Growth arrest, increased SA-β-gal positive staining, senescence-associated gene overexpression‎, deletion in mitochondrial DNA
	H2O2 induced premature senescence386,387	Increased SA-β-gal positive staining, irreversible G1 cell cycle arrest, telomere shortening, and increased p21 and gadd45 expression‎
	Tert-butylhydroperoxide (t-BHP) induced premature senescence model388	Growth arrest, increased SA-β-gal positive staining, the presence of the common 4977-bp mitochondrial deletion, overexpression‎ of p21waf-1 and the subsequent inability to phosphorylate pRb, increased senescence-associated genes expression‎
	Ethanol induced premature senescence model389,390	Growth arrest, increased SA-β-gal positive staining, overexpression‎ of p21waf-1 and the subsequent inability to phosphorylate pRb, the presence of the common 4977-bp mitochondrial deletion, increased senescence-associated genes expression‎
	Hyperoxia induced model391,392	Irreversible G1 cell cycle arrest, telomere shortening, increased protein degradation, increased lipofuscin/ceroid formation, and accumulation
Oncogene-induced senescence (OIS)	Mos-overexpression‎ model393	The growth arrest DNA damage, upregulation of p16INK4a, and increased SA-β-gal positive staining
	B-RAF V600E model394,395	Cell cycle arrest, upregulation of p16INK4a, and increased SA-β-gal positive staining
	H-RAS G12V model396,397	Upregulation of p16INK4a, low phosphorylated Rb, increased SA-β-gal positive staining
DNA methyltransferases inhibitor	5‐aza‐2′‐deoxycytidine induced model	Growth inhibition, increased SA‐β‐gal,398 increased p16, decreased p53399
Telomerase activity inhibitor	SYUIQ-5 induced model	Growth inhibition, increased SA‐β‐Gal, increased p16, p21, p27400
	Cyclin E overexpression‎ model401,402	Cell cycle arrest, DNA damge, and increased SA-β-gal positive staining
	IMR90 ER: RAS model403	The growth arrest, increased SA-β-gal positive staining and SASP markers
Elder donors derived aging models	iPSC-derived neuron with senescence phenotype404,405	iPSC-derived neurons from elder donors have senescence-related gene expression‎
	Induced neuron with senescence phenotype406,407	Induced neurons from fibroblast of elder donors have age-dependent transcriptomic signatures
In vivo models
SAMP models	SAMP6 (senile osteoporosis model)408,409,410	Decreased bone formation, and increased bone marrow adiposity, proliferator activator γ (PPARγ), and crimp-related protein 4 (Sfrp4)
	SAMP8 (AD model)301	Age-related learning and memory deficits, amyloid-β deposition, abnormal autophagy activity
	SAM10 (neurodegenerative disease model)411	Spontaneous brain degeneration leading to impairments in learning and memory as well as emotional disturbances
Physicochemical induced aging model	D-Galactose induced model299,412	Increased ROS, SA-β-gal positive staining, inflammation level, apoptosis, up-regulations of P53 and P21 genes expressions, and mitochondrial dysfunctions
	D-galactose and AlCl3 induced AD model413	Memory deficit, neuronal damage and caspase-3 overexpression‎ in the hippocampus
	D-galactose and NaNO2 induced AD model414	Increased oxidative stress, neuronal damage in the CA1, CA3, and CA4 regions of the hippocampus, impaired cognitive function, memory impaired, deterioration of sperm quality and testicular morphology
	AlCl3 induced model413,415	A notable decline in cognitive function characterized by impaired short-term memory, heightened anxiety, and a decline in spatial and reference memory
	iron radiation induced model416	Increased SASP marker, SA-β-Gal, IL-8 and persistent DNA damage responses
	O3 induced model	Including thymic atrophy, decreased body weight and exploratory activity, and increased oxidative damage
Premature aging models (WS)	Wrn−/− Terc−/− model417	Changes associated with aging include the shortening of telomeres, the onset of hair graying, alopecia, cataracts, malignancies, osteoporosis, and type II diabetes
	WrnΔhel/Δhel model412	Severe cardiac interstitial fibrosis, insulin resistance, hypertriglyceridemia, increased ROS, oxidative DNA damage, cancer incidence, and shortened lifespan
Premature aging models (HGPS)	LmnaL530P/L530P model418	Severe growth retardation, hair loss, osteoporosis, muscle atrophy
	LmnaHG/+ model419	Slow growth, osteoporosis, hair loss, partial fat malnutrition
	LmnaG609G/G609G model420	Infertility, weight loss, growth retardation, spinal curvature, calcification of blood vessels, decreased bone density, and insulin-like growth factor
	Zmpste24-/- model421	Dilated cardiomyopathy, lipodystrophy, muscular dystrophy, severe growth retardation, and premature death,
Other premature aging phenotype	BubR1H/H model422	Gliosis in the brain, arrhythmias, cataracts, hunchbacks, lipodystrophy, thinning of the skin, impaired vascular elasticity and fibrosis, and shortened life expectancy
	Ndufs4−/− model (a progressive neurodegenerative phenotype with leigh syndrome)423	Lethargy, ataxia, weight loss, premature death
	ERCC1−/− or Δ/− model424,425	Growth retardation, ataxia, loss of visual acuity, cerebellar hypoplasia, encephalopathy, kidney failure, proteinuria
	Sod1−/− model426	Muscle atrophy, fat metabolism disorders, hearing loss, cataracts, thinning of the skin, and defects in wound healing
	Klotho−/− model427,428	Arteriosclerosis, cardiovascular injury, infertility, short lifespan, skin atrophy, osteoporosis, and emphysema
	XpdTTD/TTD model429	Early graying, osteoporosis, cachexia, kyphosis, osteosclerosis, sterility, and shortened lifespan
	PolG model (mutation in mtDNA Polγ)430,431	Alopecia, anemia, weight loss, hearing loss, reduced bone mineral density, and cardiomyopathy
	PolgAmut/mut model432	Anemia, enlarged heart, osteoporosis, spine curvature, and reduced fertility
	Nfkb1−/− model303	Shortened lifespan, kyphosis, osteoporosis, tissue inflammation, and gliosis of the central nervous system
	Terc−/− model433,434	Shortened lifespan, reduced fertility, tissue atrophy, and impaired organ functions
	3xTg-AD model (AD model)435,436	Memory impairment, cognitive deficits, synaptic dysfunction, abnormal hyperexcitation of hippocampal neurons, amyloid plaques, and p-Tau accumulation
	Tg2576 model (AD model)437,438	Cognitive impairment, memory loss, oxidative lipid damage and inflammation in the brain
Longevity models	Naked mole-rats439,440	As they age, no significant increase in mortality is observed and they retain basic physiological function. They age with health and this anti-aging properties make them as a good model for aging research.
	Planarians309	With significant regenerative powers, planarians are considered immortal, DNA efficient repair mechanism, strong telomerase activity
	Salamander	Strong ability to regenerate, clearance of senescent cells,
	Turtle	Clearance of ROS, strong telomerase activity, Efficient DNA repair mechanism
Transgenic delayed aging model	Ames dwarf mice (Prop1df/df)	Prop1 gene recessive point mutation, impaired pituitary development smaller body size, PI3K/Akt/mTOR pathway downregulation441
	Snell dwarf mice (Pit1dw/dw)	Pit1 gene spontaneous mutations, impaired pituitary development, smaller body size, reduced immunosenescence442

1. A

Full size table

In vivo models

The mouse has quickly emerged as the preferred mammalian model organism in aging research. This is primarily attributed to several factors, including its relatively short lifespan compared to humans, the close similarity of its genome and physiology to humans, and the ease with which its genetics can be manipulated, including the availability of various mutant strains. These advantages make mice an excellent model for studying the aging process and investigating potential interventions and treatments for age-related conditions.297 Mouse models of accelerated aging involve physically induced models (e.g., radiation and O3), chemically induced models (e.g., D-galactose and D-galactose-combined therapy), “senescence-prone” mice (e.g., SAMP), and premature aging models (e.g., HGPS) (Table 2).

Induced or genetic aging models

In physically induced models, the inhalation of ozone is a frequently employed technique for inducing premature senescence. When male BALB/c mice are exposed to ozone at a concentration of 1.2 mg/m3 for 10 h per day, they exhibit thymic atrophy and an elevated level of oxidative damage. Subsequently, there is a decline in the immune function of the mice, which is closely associated with oxidative stress. This decline is characterized by an increase in IL-6 levels, reduced splenocyte proliferation, decreased production of IL-2, diminished natural killer (NK) cell activity, and a weakened antigen-specific response.298

For chemical induction models, the D-galactose-induced aging model is widely preferred in chemical induction studies due to its convenience, higher survival rate, and minimal side effects. This model effectively mimics aging in vivo by inducing changes in various tissues and organs. When mice are treated with certain concentrations of D-galactose, they exhibit increased levels of ROS and inflammatory cytokines such as NOS-2, IL-1β, IL-6, TNF-α, and NF-κB. These alterations contribute to the aging-like phenotype observed in this model. Moreover, researchers have developed combined methods involving D-galactose to induce premature aging. For instance, the D-galactose and AlCl3 model and the D-galactose and NaNO2 model are commonly used. These combinations enhance the aging effects and provide additional insights into the mechanisms underlying accelerated aging.299

Senescence-accelerated mouse/prone (SAMP) strains, specifically the SAMP1/Yit substrain, have been recognized as valuable models for studying the genetic aspects of aging. In particular, the SAMP1/Yit mice have been used as a model for Crohn’s disease, which is a chronic and recurring inflammatory bowel disease. The mice exhibit both acute and chronic inflammation in the ileum and cecum, displaying a non-continuous pattern of inflammation.300 On the other hand, the SAMP8 mouse strain is considered an excellent model for investigating Alzheimer’s disease (AD), a cognitive decline disorder that predominantly affects the elderly. The SAMP8 mice exhibit reduced expression‎ and lower activity of anti-aging factors including silent information regulator type (sirtuin/Sirt), Forkhead box class O (FoxOs), and Klothos. These factors play crucial roles in the aging process.301

Aging models with apparent inflammation phenotypes include Nfkb1 deficient mice (Nfkb1−/−). Nfkb1−/− mice have shortened lifespan, kyphosis, osteoporosis, tissue inflammation, and gliosis of the central nervous system.302 Interestingly, the accumulation of senescent cells with telomere-dysfunction in Nfkb1−/− tissues can be effectively hindered through the implementation of anti-inflammatory or antioxidant treatment in mice.303 This noteworthy observation underscores the promising utilization of these mice as valuable models for investigating age-related interventions. Details of other in vivo aging models are also shown in Table 2.

Premature aging models

Premature aging models can be categorized into two main types: progeroid syndrome models and other models exhibiting premature aging phenotypes. Progeroid syndromes are exceptionally uncommon human disorders characterized by early onset aging and a reduced lifespan. These syndromes include laminopathies, such as Hutchinson-Gilford progeria syndrome (HGPS), which disrupt the balance of the nuclear envelope, as well as conditions that affect telomere length and DNA repair mechanisms, like Werner syndrome and Cockayne syndrome.

The identification of specific mutations causing these syndromes has enabled the development of mouse models that simulate premature aging.304 For instance, mouse models of HGPS have been created by modifying the Lmna gene or its processing enzyme. Among these models, the LmnaG609G mouse model (featuring the mutation 1827C > T; Gly609Gly) closely resembles human phenotypes.305 This includes heightened inflammation markers like IL-6, caspase 1, and Nlrp3, increased oxidative stress, persistent DNA damage, and cell cycle arrest.306,307 In addition, two independently generated mouse models deficient in the Zmpste24 gene (Zmpste24 − /− mice) also exhibit elevated expression‎ of caspase 1 and Nlrp3, severe growth retardation, dilated cardiomyopathy, muscular dystrophy, lipodystrophy and premature death.307,308

Classic longevity animal model

Many animals naturally have long lifespans. Decoding the underlying mechanisms for provide insights for developing anti-aging strategies. One such remarkable example is the naked mole rat, a socially oriented mammal that dwells in subterranean burrows. This extraordinary creature holds the esteemed distinction of being the longest-living rodent, with a maximum lifespan that surpasses an astonishing 30 years.309 With aging, naked mole rats will not lose their physiological functions, and their mortality will not increase significantly.310 As a successful aging specifications, nude mole also achieved resistance to tumor through a variety of methods, such as efficient DNA damage repair, synthesis of unique anti-inflammatory high molecular weight hyaluronan.311 The special longevity mechanism of naked mole makes it a good animal model for longevity research and provides a blueprint for exploring the strategies of delaying human aging.

Planaria is a type of flatworms. For planarians, small fragments of almost any tissue can be regenerated into an entire individual. This has led it to be considered immortal. The shortening of telomeres during cell division is a major obstacle to infinite cell division, and planarians overcome this problem by upregulating telomerase expression‎ during regeneration.312 On the other hand, planarians also achieve resistance to tumors through a variety of means, such as efficient DNA repair mechanisms.313 All of these mechanisms provide enlightenment for us to study human aging.

As an amphibian, the salamander is also very long-lived. Their limbs and many of their organs are capable of regenerating. Axolotls age very slowly, and their phenotypes are less pronounced. Its physiological mechanism to clear senescent cells in time prevents senescent cells from accumulating in its body, which may explain its slow aging.314 The salamander’s large genome may have provided lines of defense for potentially harmful mutations, such as regulators. This also laid the foundation for the prevention of tumors.315

Turtles are a typical group of long-lived animals. The protection of the carapace keeps them from predators. During diving, turtles are chronically deprived of oxygen, which allows them to upregulate glutathione-related enzymes to clear away ROS.316 Inhibition of ROS and unique telomerase and perhaps DNA repair mechanisms make turtles’ longevity possible.317

Centenarian human models

Unlike artificial models, the centenarian model, as a naturally occurring model, has become an indispensable tool for human beings to decipher longevity. Unlike other people, centenarians have significantly different levels of hormones, cholesterol, etc. in their bodies. Inflammation levels in centenarians show a better balance compared to others, and therefore inflammation levels have been used to predict healthy lifespan. The offspring of centenarians also typically maintain lower levels of chronic inflammation in their bodies, and these lower levels can increase as the centenarian ages, but ultimately those who can maintain lower levels of inflammation may have the best chance of maintaining their bodies in good health. This suggests that genes may be a key factor in maintaining low levels of inflammation in centenarians.6 In addition, the low susceptibility of centenarians to diseases raises the question of whether their immune system is stronger. Studies have shown lower levels of B cells, similar numbers of T cells, and a higher percentage of cytotoxic T cells in the peripheral blood of supercentenarians.318 Compared with animal models, the centenarian model can more realistically reflect the changes in human organs as well as peripheral blood components and has indispensable reference value for human anti-aging research. In conclusion, the long-lived elders are the result of “natural experiments”. They show us that it is possible for individuals to live longer and healthier lives, even if they are influenced by risky genes or if they choose to ignore health information on their own.

Cutting-edge single-cell technology

Single-cell technology reveals organismal activity at the level of the genome, epigenome, transcriptome, proteome, and metabolome. A recent achievement of single-cell technology in the aging field is an aging atlas in different species at a multi-omics level, which allows us to understand aging with a more systemic view.

Aging is extremely heterogeneous, especially from a transcriptome perspective.198 The aging transcriptome landscape in mouse, rat, and cynomolgus monkey is presented in Table 3, including samples, time, platform, cell numbers, and main conclusions. In the future, spatial single-cell technologies (spatial transcriptome and spatial metabolome) make it possible to construct three-dimensional aging atlases at the organ level.319

Table 3 Single cell landscape of aging in mouse, rat and cynomolgus monkey

Full size table

Intervention strategies in aging

Lifestyle interventions

A healthy lifestyle has long been recognized as the most effective way to maintain health and fight aging.320 More and more research has proven that maintaining a healthy lifestyle, such as adequate nutrition,321 moderate exercise,322 and good mental state323 can effectively delay aging. Balanced and adequate nutrition intake has a positive effect on aging. Many of the nutrients that people take in, such as minerals, probiotics, etc., play an important role in alleviating inflammation and regulating immunity. Long-term polyphenyl-rich dietetic pattern has been proved to improve intestinal permeability and the level of inflammatory markers.324 Previous studies have also proved that the intake of probiotics, such as Lactobacillus pentosus var. plantarum C29, has been proved to significantly reduce the level of systemic inflammatory factors and the expression‎ of aging markers p16 and p53.325 Similarly, consumption of polyunsaturated fatty acids has been shown to significantly reduce levels of inflammatory cytokines throughout the body326 The continuous intake of vitamins, such as vitamin C and vitamin E, can effectively improve the function of immune cells in the elderly, Such as the chemotaxis and phagocytosis of neutrophils.327 The supplementation of minerals, such as zinc, can increase the naive T cell subgroup328 and improve the homeostasis of Th1 and Th2 cells.329 These all emphasize the importance of maintaining balanced nutrition intake.

Exercise is an efficient strategy for delaying aging330 through various mechanisms, such as DNA damage331 and oxidative stress.332 Recent study found that middle-aged marathon/triathletes had higher telomerase activity and longer telomere length in circulating white blood cells compared to the control group.333 Correspondingly, resistance training for five months in older overweight or obese women reduced the number of P16-expressing cells in their thigh fat tissue.334 These evidence suggest that exercise can effectively reduce the appearance of age-related markers, such as p16, so as to achieve the effect of delaying aging.

Keeping a good mental state can also delay aging. Psychological stress affects neuroendocrine function through hypothalamus-pituitary-adrenal axis.335 The continuous activation of this circuit leads to the continuous increase of glucocorticoid level, which will lead to hippocampal atrophy, a phenomenon closely related to aging.323 In addition. A longitudinal study found that the elevation of inflammatory markers increased in elderly people with high self-reported stress levels during follow-up. This may reflect the internal relationship between psychological stress and inflammation.336 These findings suggest that improving mental health and alleviating psychological stress have a positive effect on aging. Lifestyle choices are closely associated with ageing. Keeping a healthy life sometimes means a longer life.

Anti-inflammation strategies

Recent studies have demonstrated that the pro-inflammatory cytokine network is one potential anti-aging target, using anti-inflammation drugs such as metformin, aspirin, rapamycin, and ibuprofen. For example, metformin can reduce chronic inflammation and improve healthy mid-life aging by acting on possible targets such as IKK/NF-κB in patients with Type 2 diabetes,337 as well as GPX7/NRF2338 and a recently found target, PEN2.339 Aspirin can postpone the occurrence of replicative senescence by decreasing oxidative stress. The latest studies have identified CD36 as key to SASP-related mechanisms and reduced SASP secretion in senescent cells by silencing CD36 in senescent muscle tissue cells using CD36-specific short interfering RNA.340 In general, current strategies of anti-inflammation and immune enhancement, including potential targets and main adaptation diseases are summarized in Table 4.

Table 4 Current intervention strategies against aging

Table 4 Current intervention strategies against aging

From: Inflammation and aging: signaling pathways and intervention therapies

StrategiesPossible targetsDevelopment statusDetails

Dasatinib (D) and Quercetin (Q)450,451	Pan-receptor tyrosine kinases; PI3K isoform and Bcl-2 family members	Phase II clinical trial (NCT02848131) for chronic kidney disease346	Dasatinib has been shown to effectively eliminate senescent human fat cell progenitors. On the other hand, quercetin has demonstrated greater efficacy against senescent human endothelial cells and mouse BM-MSCs. When used in combination (D + Q), these two drugs induce apoptosis more efficiently by targeting a larger number of senescent cell-associated phenotypes (SCAPs) compared to either drug used alone. This synergistic effect has been observed in various types of senescent cells.
Metformin365,452,453	IKK and/or NF-κB; AMP-activated protein kinase activity; Glutathione peroxidase 7 (GPx7) and nuclear factor erythroid 2-related factor 2 (Nrf2)	Approved for type 2 diabetes454,455	Metformin exerts its effects by preventing the translocation of NF-κB to the nucleus and inhibiting the phosphorylation of IκB and IKKα/β. In addition, it enhances the activity of AMP-activated protein kinase, leading to reductions in both the accumulation of oxidative damage and chronic inflammation. Metformin upregulates the endoplasmic reticulum localized GPX7 and increases the nuclear accumulation of Nrf2. Metformin-Nrf2-GXx7 pathway delays aging.
Rapamycin456	mTOR	Approved by the FDA for the prevention of organ rejection following kidney transplantation and the treatment of lymphangioleiomyomatosis457,458,459	The TOR (target of rapamycin) kinase restricts longevity through mechanisms that are not fully understood. Rapamycin, a compound that inhibits the mammalian TORC1 complex responsible for regulating translation, has been shown to increase lifespan in various species, including mice. Our research demonstrates that rapamycin specifically attenuates the inflammatory characteristics exhibited by senescent cells.
Fisetin460,461	Glutathione; mitochondria; Key neurotrophic factor signaling pathways; Lipoxygenases and pro-inflammatory eicosanoids and their by-products	Preclinical animal models	Fisetin exhibits direct antioxidant activity and enhances intracellular levels of glutathione, the primary antioxidant within cells. Furthermore, it preserves mitochondrial function when faced with oxidative stress. In addition, it inhibits lipoxygenase activity, thereby decreasing the production of pro-inflammatory eicosanoids and their derivatives. Overall, fisetin helps mitigate the effects of age-related neurological disorders on brain function.
Curcumin462,463	Nrf2 and NF-κB pathways	Preclinical animal models	Curcumin has been found to exhibit senolytic properties against senescent human intervertebral disc (IVD) cells by downregulating the Nrf2 and NF-κB pathways. The application of curcumin and o-Vanillin effectively eliminated senescent IVD cells and mitigated the SASP, which is linked to inflammation and back pain. This research highlights the potential of curcumin in targeting senescent cells and alleviating the negative consequences associated with senescence in the intervertebral discs.
Piperlongumine464,465,466,467	Oxidation resistance 1 (OXR1); NF-κB signaling pathway	Preclinical animal models	Piperlongumine exerts its effects through two distinct mechanisms. Firstly, it selectively induces the death of senescent cells by directly binding to oxidation resistance 1 (OXR1), resulting in its degradation through the proteasomal pathway. This degradation of OXR1 leads to an increase in ROS production within the cells. Secondly, Piperlongumine inhibits the growth of lung tumors by targeting the NF-κB signaling pathway. Overall, these actions of Piperlongumine demonstrate its potential as a promising therapeutic agent for targeting senescent cells and inhibiting tumor growth in the lungs.
Aspirin468,469,470	NO; Telomerase	Approved	Aspirin has been shown to inhibit senescence and SASP, providing a potential mechanism for its beneficial effects on healthy aging. For instance, aspirin has been found to delay the onset of replicative senescence in endothelial cells. This effect is achieved by increasing nitric oxide synthesis and reducing oxidative stress, ultimately leading to the upregulation of telomerase activity.
Fenofibrate347	PPARα	Preclinical animal models	In investigations involving human osteoarthritis and aging primary chondrocytes, the administration of fenofibrate exhibited several beneficial effects. Specifically, fenofibrate treatment upregulated the expression‎ of PPARα, resulting in reduced chondrocyte senescence. Moreover, it increased autophagic flux and induced the selective elimination of senescent cells.
CAR-T/NK	uPAR; FAP	Preclinical animal models	CAR-T cells targeting uPAR and FAP can effectively clear senescent cells, while CAR-T cells targeting FAP can further reduce the extent of cardiac fibrosis. Adoptive NK cell infusion also successfully reduced senescence markers and SASP levels.

1. IKK IkappaB kinases, NF-κB nuclear factor kappa-B, AMP adenosine monophosphate, GPX7 glutathione peroxidase 7, NRF2 nuclear factor erythroid 2-related factor 2, PEN2 PENETRATION2, Nrf2 nuclear factor E2-related factor 2, SASP senescence-associated secretory phenotype, OXR1 oxidation resistance 1, ROS reactive oxygen species, NO nitric oxide, NMDA N-methyl-D-aspartate, MAPK mitogen-activated protein kinase, ERK1/2 extracellular signal-regulated kinase 1/2, IFN interferon, CDK4/6 cyclin-dependent kinases 4 and 6, PI3K phosphatidylinositol-4,5-bisphosphate 3-kinase, SCAPs senescent cell anti-apoptotic pathways, PPARα peroxisome proliferator-activated receptor alpha, MSC mesenchymal stem cell

Full size table

Senolytic drug for eliminating senescent cells

Of all the anti-ageing cell therapies, Senolytics (removal of senescent cells) are the most well-developed and specific but also the most controversial. Since 2015, several Senolytics have gone from identification to clinical trials. The first Senolytics-like drug combination was Dasatinib and Quercetin. Dasatinib removes senescent human adipocyte progenitor cells, while Quercetin is more potent in killing senescent human endothelial cells and bone marrow stem cells in mice.341 The most potent removal of senescent cells was achieved when these two compounds were combined. In several mouse experiments, the treatment alleviated inflammation342 and age-related diseases of the intestines343 and bone.344 In the first human trial, ‘Dasatinib + Quercetin’ treatment increased patients’ 6-minute walking distance by an average of 21.5 meters. However, other indicators including Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health did not change significantly.345 Further research is needed on the core indicators such as SASP levels which will also predict efficacy and side effects over time. In clinical trials in patients with diabetic nephropathy, Dasatinib, and Quercetin significantly reduced senescent cell levels as well as circulating SASP levels over 11 days.346 Considering the potential toxicity of the inflammation produced by cell death and grab, there is a lack of long-term follow-up studies for this therapy and the current evidence is insufficient to support its long-term anti-aging effectiveness. In addition, another Senolytic called Fenofibrate can induce selective elimination of senescence cells through upregulating PPARα expression‎.347 Excessive clearance of senescent cells (especially for senescent liver sinusoidal endothelial cells or adipocytes) has also been reported to accompany the dilemma faced by cells that cannot be replenished in time, although Quercetin + Dasatinib clears mainly p16 macrophages.348

(CAR-)T/NK for eliminating senescent cells

On the other hand, immune cell-mediated clearance of senescent cells is emerging as a promising strategy to fight multiple chronic diseases and aging.349 It was found that anti-uPAR-CAR-T cells were effective in removing senescent cells in vitro and pre-cancerous and malignant cells in mouse models of liver and lung in the presence of potentially toxic.350 Previously, CAR-T therapy targeting FAP was found to significantly reduce cardiac fibrosis and improve heart function. Surprisingly, FAP-CAR-T cells did not target other normal cells in the body and did not cause recruitment and infiltration of immune cells and increased levels of inflammatory factors, such as IL-1 and IL-6.351 In addition, clearance of senescent cells by NK cell-based immune cells prolongs the lifespan of mice and appeared to be safer.352 In the aged mice and healthy/obese volunteers, adoptive NK cell infusion significantly reduced senescence markers and SASP levels without significant toxic side effects.353,354 In addition, their combination with the immunomodulatory factor Acein significantly decreased the expression‎ of tissue senescence markers and age-related genes in a mouse model of senescence.353

Stem cell therapy

Stem cell therapy has become an effective strategy for the treatment of aging-related diseases. Many studies have shown that the number and function of different somatic cell populations declines with age, which diminishes the regenerative potential of tissues and organs. However, there is limited evidence that loss of stem cell function is a major driver of age-related pathology and shortened lifespan.355,356,357,358 Trials have found that after stem cell injections in aging debilitated patients, many symptoms improve, and inflammatory marker levels decrease.359 MSC transplantation for acute stroke improves patient symptoms and promotes neurological recovery in ischemic stroke patients without adverse effects.360,361,362 Meanwhile, mesenchymal stem cell transplantation for Parkinson’s disease can significantly improve the daily activities and motor functions of Parkinson’s disease patients without side effects, as well as being safe and reliable.363,364 In addition, HSC transplantation is a very rapidly and effective clinical treatment for age-related diseases such as AML.

Organ regeneration and transplantation

Similar to stem cell transplantation, organ transplantation is a very effective anti-aging modality because it can “repair” the damage caused by aging in the most simple and brutal way. For example, many risk indices for age-related diseases were improved after thymic regeneration in humans (taking three commonly used drugs: growth hormone, dehydroepiandrosterone, and metformin),365 and biological age was reversed.366 However, in order to use this technology in the field of anti-aging, two problems must first be solved: the shortage of spare organ stock and rejection after transplantation. Currently, most donated organs come from relatives, cerebrally dead donors, or even animals. For organs from old donors, Senolytics are used to rejuvenate aging organs.367 Meanwhile, the world’s first “transplantation” of a porcine heart into a human was initially successful and has not caused hyperacute rejection in humans. If animal organs are successfully transplanted and the cost is controlled, human disease treatment and anti-aging will take a step forward.

Resistance and reversal of aging is the ultimate goal of aging research. Anti-inflammation, removal/improvement of senescent cells, stem cell therapy and organ transplantation have become crucial ways to reverse aging in humans.

Discussion

The global population has been experiencing an aging trend, and the elderly population is more susceptible to infections, increased mortality, and morbidity.368,369 Chronic inflammation appears to be closely linked to aging, and this review focuses on inflammaging, providing an overview of the molecular, cellular, and organ levels of the human body. At the cellular level, external DAMPs activate different immune cells, promoting inflammation and leading to immunosenescence. Dysfunctional immune cells cannot clear senescent cells in a timely manner, leading to inflammation and the development of aging-related diseases and/or normal aging in different organs (Fig. 1). In addition to the separate analysis of molecules, cells, and organs, we also hope to closely link the cells, organs and molecule with single-cell multi-omics (including genome, transcriptome, epigenome, proteome and metabolome) and spatial omics.

The construction of animal models is an effective way to study aging (Table 2). The present review systematically summarizes the characteristics of different aging models, both in mice and in vitro cell lines. To date, an aging atlas of the whole organ has been profiled in mice. Considering the differences between different species,370 it will be important to construct non-human primate and human aging models in the future. In addition, several resource tools have been developed to assist in aging research, such as SeneQuest to promote the discovery of genes associated with senescence (available at http://Senequest.net).371 On the other hand, other technologies, such as machine learning which integrates multi-modal and multidimensional big data, are also important to address the complexity of aging problems (Table 4). A recent paper summarizes the development and application of aging clocks with the help of machine learning analysis of histological data. This illustrates the ability of machine learning to identify novel biomarkers of biological aging and provides a boost to early warning and intervention in aging and precision medicine strategies.372 In 2022, Li et al. developed Nvwa, a deep-learning-based strategy, which predicts gene expression‎ and identifies conserved regulatory programs underlying cell types at the cross-species single-cell level.373 In the future, we also hope to find similar cross-species conservative regulatory elements in the aging process through development of machine learning algorithms.

The immune system has a remarkable ability to remember and respond to different stimuli and experiences, leading to heterogeneity in immunosenescence among individuals. This heterogeneity can result from differences in the type, dose, intensity, and temporal sequence of antigenic stimuli to which each person is exposed. To address this issue, Franceschi et al. proposed the concept of “immunobiography,” which considers the unique history of antigenic exposure that shapes an individual’s immune system over time.374 While immunobiography provides a comprehensive framework for understanding immune aging, it does not take into account other factors that can influence the accumulation of inflammation and the aging process, such as genetics and social factors. Therefore, a more holistic approach that considers multiple factors may be necessary to fully understand the complexities of immunosenescence and inflammaging.

Preventing and alleviating the diseases of aging and improving quality of life are the ultimate goals of aging research. Current anti-aging strategies include eliminating senescent cells, stem cell therapy, and organ transplantation, whose essence is anti-inflammatory. However, what came first, the aging (chicken) or the inflammation (egg)? The exact causality between inflammation and aging deserves further studies for efficient intervention of aging-associated diseases and enhancing well-being.

References

1.  
2.  
3.  
4.  
5.  
6.  
7.  
8.  
9.  
10.  
11.  
12.  
13.  
14.  
15.