Cellular senescence and senolytics: the path to the clinic 2022 natur 리뷰

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• Review Article
• Published: 11 August 2022

Cellular senescence and senolytics: the path to the clinic

• Selim Chaib, 
• Tamar Tchkonia & 
• James L. Kirkland 

Nature Medicine volume 28, pages1556–1568 (2022)Cite this article

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Abstract

Interlinked and fundamental aging processes appear to be a root-cause contributor to many disorders and diseases. One such process is cellular senescence, which entails a state of cell cycle arrest in response to damaging stimuli. Senescent cells can arise throughout the lifespan and, if persistent, can have deleterious effects on tissue function due to the many proteins they secrete. In preclinical models, interventions targeting those senescent cells that are persistent and cause tissue damage have been shown to delay, prevent or alleviate multiple disorders. In line with this, the discovery of small-molecule senolytic drugs that selectively clear senescent cells has led to promising strategies for preventing or treating multiple diseases and age-related conditions in humans. In this Review, we outline the rationale for senescent cells as a therapeutic target for disorders across the lifespan and discuss the most promising strategies—including recent and ongoing clinical trials—for translating small-molecule senolytics and other senescence-targeting interventions into clinical use.

서로 연결되어 있는 근본적인 노화 과정은 많은 장애와 질병의 근본 원인으로 작용하는 것으로 보입니다. 이러한 과정 중 하나는 세포 노화이며, 

세포 노화는 

유해한 자극에 반응하여 

세포 주기가 정지되는 상태를 수반합니다. 

노화 세포는 

전 생애에 걸쳐 발생할 수 있으며, 

지속될 경우 분비되는 많은 단백질로 인해 

조직 기능에 해로운 영향을 미칠 수 있습니다. 

전임상 모델에서 

지속적이고 조직 손상을 유발하는 노화 세포를 표적으로 하는 중재는 

여러 장애를 지연, 예방 또는 완화하는 것으로 나타났습니다. 

이에 따라 

노화 세포를 선택적으로 제거하는 

저분자 노화 분해 약물의 발견은 

인간의 여러 질병과 노화 관련 질환을 

예방하거나 치료하는 유망한 전략으로 이어졌습니다. 

이 리뷰에서는 

노화 세포를 

전 생애에 걸친 질환의 치료 표적으로 삼을 수 있는 근거를 설명하고, 

저분자 노화 분해제 및 기타 노화 표적 개입을 임상으로 전환하기 위한 

가장 유망한 전략(최근 및 진행 중인 임상시험 포함)에 대해 논의합니다.

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Main

The aging population is steadily increasing. The World Health Organization (WHO) estimates that 1 in 6 people, or 2.1 billion, are expected to be over age 60 by 2030 (ref. 1). Chronological age is the major predictor for most of the diseases that account for the bulk of morbidity, mortality and health costs across low-, middle- and high-income countries2,3,4,5,6,7.

Aging progresses throughout the lifespan can be accentuated at etiologic sites of multiple acute and chronic diseases, including in children6,8,9,10,11,12. Indeed, fundamental aging processes can operate even before conception, for example, in the context of aged oocytes linked to Down syndrome12,13. A fundamental aging mechanism that has gained increasing attention is cellular senescence. Senescent cells accumulate during aging and at pathogenic sites of multiple disorders and diseases. After the first reports of senolytic drugs (agents that selectively eliminate senescent cells) in 2015 (ref. 14), promising results from preclinical studies have facilitated progression to early-phase clinical trials eval‎uating the safety and efficacy of senolytics, some of which have now been published (Table 1).

고령화 인구는 꾸준히 증가하고 있습니다. 세계보건기구(WHO)는 2030년에는 인구 6명 중 1명, 즉 21억 명이 60세 이상이 될 것으로 예상하고 있습니다(참고 1). 연령은 저소득, 중산층 및 고소득 국가에서 이환율, 사망률 및 의료 비용의 대부분을 차지하는 대부분의 질병에 대한 주요 예측 인자입니다2,3,4,5,6,7.

전 생애에 걸쳐 진행되는 노화는 어린이를 포함한 여러 급성 및 만성 질환의 병인 부위에서 두드러지게 나타날 수 있습니다6,8,9,10,11,12. 실제로 근본적인 노화 과정은 다운 증후군과 관련된 노화된 난모세포의 맥락에서 임신 전에도 작동할 수 있습니다12,13.

 최근 주목받고 있는 근본적인 노화 메커니즘은 

세포 노화입니다. 

노화된 세포는 

노화 과정과 

여러 장애 및 질병의 병원성 부위에 축적됩니다. 

2015년 

노화 세포를 선택적으로 제거하는 약제인 

노화 용해제가 처음 보고된 이후(참고 14), 

전임상 연구의 유망한 결과로 인해 

노화 용해제의 안전성과 효능을 평가하는 초기 단계 임상시험으로 진행되었으며, 

그 중 일부는 현재 발표되었습니다(표 1).

한약재.. 케르세틴, 피제틴..

Table 1 Senolytic clinical trials: completed, current or planned

Full size table

Fundamental aging mechanisms can be grouped into so-called hallmarks or ‘pillars’ of aging; these include genomic instability, progenitor cell exhaustion/dysfunction, telomeric and epigenetic changes, dysregulated protein homeostasis, altered nutrient sensing, mitochondrial dysfunction, altered intercellular communication, chronic low-grade inflammation, fibrosis, microbiome dysregulation and cellular senescence3,15. The Geroscience Hypothesis holds that these pillars of aging, including cellular senescence, tend to progress in concert and may be root-cause contributors to the pathophysiology of multiple diseases, age-related dysfunction (including the geriatric syndromes such as frailty, immobility, sarcopenia/muscle wasting, mild cognitive impairment and incontinence) and loss of resilience (for example, decreased ability to recover from stresses such as injury, surgery, chemotherapy or infections or to mount an antibody response to immunizations)3,15,16,17,18. The Unitary Theory of Fundamental Aging Mechanisms builds on the Geroscience Hypothesis by positing that interventions targeting any one fundamental mechanism may target the others6. For example, interventions that target cellular senescence tend to attenuate other fundamental aging mechanisms leading to reduced inflammation, attenuated exhaustion of progenitors, decreased fibrosis, alleviated mitochondrial dysfunction and a partially restored microbiome in experimental animal models of aging and chronic diseases6,7,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36.

근본적인 노화 메커니즘은 

소위 노화의 특징 또는 '기둥'으로 분류할 수 있는데, 

여기에는 

게놈 불안정성, 

전구세포 고갈/기능 장애, 

텔로미어 및 후성유전학적 변화, 

단백질 항상성 조절 장애, 

영양소 감지 장애, 

미토콘드리아 기능 장애, 

세포 간 통신 장애, 

만성 저등급 염증, 

섬유증, 

마이크로바이옴 조절 장애 및 세포 노화가 포함됩니다3,15. 

참고) 자극, 감작--> 영양소 감지장애, 세포간 통신장애, 단백질 항상성 조절장애 .... 미토콘드리아 기능장애.. 만성염증... 게놈불안정성, 전구세포 기능장애, 텔로미어 및 후성유전학 변화... 마이크로 바이옴 조절장애.. 세포 노화...

노화과학 가설에 따르면 

세포 노화를 포함한 이러한 노화의 기둥은 함께 진행되는 경향이 있으며, 

여러 질병의 병태생리, 

노화 관련 기능 장애(허약, 노쇠, 근감소증과 같은 노인 증후군 포함), 

노화 관련 기능 장애의 근본 원인이 될 수 있다고 합니다, 

부동, 근감소증/근육 소실, 경도 인지 장애, 요실금 등) 및 회복력 상실(예: 부상, 수술, 화학 요법 또는 감염과 같은 스트레스에서 회복하거나 예방 접종에 대한 항체 반응을 일으키는 능력 감소)3,15,16,17,18)의 근본 원인이 될 수 있습니다. 근본적인 노화 메커니즘의 단일 이론은 하나의 근본적인 메커니즘을 표적으로 하는 개입이 다른 메커니즘을 표적으로 할 수 있다고 가정함으로써 노화 과학 가설에 기반을 두고 있습니다6. 

예를 들어, 

세포 노화를 표적으로 하는 개입은 

다른 근본적인 노화 메커니즘을 약화시켜 

노화 및 만성 질환의 실험 동물 모델에서 염증 감소, 전구세포의 소진 완화, 섬유증 감소, 미토콘드리아 기능 장애 완화 및 부분적인 마이크로바이옴 회복으로 이어지는 경향이 있습니다6,7,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36.

By understanding and targeting cellular senescence and the other pillars of aging, rather than targeting individual diseases that are downstream of fundamental aging processes, it is conceivable that multimorbidity could be reduced and healthspan increased, with realization of substantial societal and economic benefits4,6. In this Review, we consider the potential value of senescent cells as a therapeutic target, the current state of senolytic drug development and the path to bring preventive and therapeutic strategies targeting senescent cells to the clinic.

근본적인 노화 과정의 하류에 있는 개별 질병을 표적으로 삼는 것이 아니라 

세포 노화와 노화의 다른 기둥을 이해하고 

표적으로 삼는다면 

다발성 이환율을 줄이고 

건강 수명을 늘려 상당한 사회적, 경제적 이익을 실현할 수 있을 것으로 생각됩니다4,6. 

본 리뷰에서는 노화 세포의 치료 표적로서의 잠재적 가치, 노화 세포를 표적으로 하는 약물 개발 현황, 노화 세포를 표적으로 하는 예방 및 치료 전략을 임상에 도입하기 위한 경로에 대해 살펴봅니다.

Cellular senescence: mechanisms and pathways

Cellular senescence was first reported in 1961 by Hayflick and Moorhead after serially subculturing human fibroblasts37. Senescent cells, which are in a state of essentially irreversible cell cycle arrest but remain viable, can accumulate with aging, especially in more frail individuals, and at pathogenic sites of multiple disorders and diseases in experimental animals and humans across the lifespan. The senescent cell fate can be triggered by a number of stressors including DNA damage, cancerous mutations or oncogene activation, mitochondrial dysfunction, reactive metabolites, hyperoxia or hypoxia, proteotoxic stress, extracellular signals, infections, mechanical or shear stresses that deform cells, resistance exercise and factors secreted by other senescent cells18,38,39,40,41,42,43,44,45,46,47. Many such stressors activate DNA damage response signaling and activation of the p53/p21CIP1/WAF1, p16INK4a/retinoblastoma protein or other pathways, resulting in cell cycle arrest and the development of a senescence-associated secretory phenotype (SASP)24,40,48,49,50,51,52,53 (Fig. 1). Through upregulation of pro-survival and antiapoptotic pathways such as SRC kinases, the PI3K–AKT signaling pathway, heat shock protein (HSP) pathways, serpines, mitochondrial pathways or apoptosis regulator BCL-2-related proteins, those senescent cells with a proapoptotic SASP can survive, despite the cytotoxic microenvironment they create6,7,14,34,35,54,55,56,57,58.

세포 노화는 

1961년 헤이플릭과 무어헤드가 

인간 섬유아세포를 연속적으로 하위 배양한 후 처음 보고했습니다37. 

본질적으로 되돌릴 수 없는 세포 주기 정지 상태에 있지만 

생존력은 유지되는 노화 세포는 

노화와 함께, 

특히 허약한 개체에서, 

그리고 실험동물과 인간의 여러 장애 및 질병의 병원성 부위에서 

전 생애에 걸쳐 축적될 수 있습니다.

 노화 세포의 운명은 

DNA 손상, 

암성 돌연변이 또는 발암 유전자 활성화, 

미토콘드리아 기능 장애, 

반응성 대사산물, 

고산소증 또는 저산소증, 

단백질 독성 스트레스, 

세포 외 신호, 

감염, 

세포를 변형시키는 기계적 또는 전단 스트레스, 

저항 운동 및 다른 노화 세포에서 분비되는 인자를 포함한 

여러 스트레스 요인에 의해 촉발될 수 있습니다18,38,39,40,41,42,43,44,45,46,47. 

이러한 많은 스트레스 요인은 

DNA 손상 반응 신호와 

p53/p21CIP1/WAF1, p16INK4a/망막모세포종 단백질 또는 

기타 경로의 활성화를 활성화하여 

세포 주기를 정지시키고 

노화 관련 분비 표현형(SASP)24,40,48,49,50,51,52,53의 발생을 초래합니다(그림 1). 

SRC 키나아제, 

PI3K-AKT 신호 전달 경로, 

열충격 단백질(HSP) 경로, 

서파인, 

미토콘드리아 경로 또는 

세포사멸 조절인자 BCL-2 관련 단백질과 같은 

친생존 및 항사멸 경로의 상향 조절을 통해 

세포독성 미세 환경에도 불구하고 

친사멸성 SASP를 가진 노화 세포가 살아남을 수 있습니다6,7,14,34,35,54,55,56,57,58.

Fig. 1: Senescence-associated secretory phenotype.

The SASP is a key feature of cellular senescence. Cellular stressors induce DNA damage response signaling, which activates key transcription factors and pathways including NF-κB, CCAAT/enhancer binding protein-β (C/EBPβ), GATA binding protein 4 (GATA4), p38 and JAK–STAT, which can drive and modulate the SASP31,48,60,63,64,103,157,214,215,216,217,218. The various forms of the SASP can comprise chemokines, extracellular matrix proteases, remodeling factors, bioactive lipids, noncoding nucleotides and reactive metabolites7,31,59,60,61,62,63,64. IL-6, interleukin-6; ROS, reactive oxygen species; TGF-β, transforming growth factor beta; TIMPs, tissue inhibitors of metalloproteinases; TNF, tumor necrosis factor.

SASP는 

세포 노화의 주요 특징입니다. 

세포 스트레스 요인은 

DNA 손상 반응 신호를 유도하여 

NF-κB, 

CCAAT/인핸서 결합 단백질-β(C/EBPβ), 

GATA 결합 단백질 4(GATA4), p38 및 JAK-STAT를 비롯한 

주요 전사인자 및 경로를 활성화하여 

SASP31,48,60,63,64,103,157,214,215,216,217,218을 구동하고 조절할 수 있습니다. 

다양한 형태의 SASP는 

케모카인, 

세포외 기질 프로테아제, 

리모델링 인자, 

생리활성 지질, 

비코딩 뉴클레오티드 및 반응성 대사산물7,31,59,60,61,62,63,64로 구성될 수 있습니다. 

IL-6, 인터루킨-6, ROS, 활성 산소 종, TGF-β, 형질 전환 성장 인자 베타, TIMP, 금속 단백질 분해 효소의 조직 억제제, TNF, 종양 괴사 인자.

The senescence-associated secretory phenotype

Most cells undergoing senescence develop a SASP (Fig. 1). In 30–70% of senescent cells, this SASP entails pro-inflammatory, proapoptotic and pro-fibrotic factors7,31,40,59,60,61,62,63,64, some of which can cause previously non-senescent cells to become senescent both locally and at a distance in an endocrine manner24,39,47. This proapoptotic SASP can have detrimental effects both locally and systemically due to senescent cell accumulation and persistence24. In the other 30–70% of senescent cells, the SASP appears to comprise growth and other regenerative factors, potentially causing less apoptosis, tissue destruction and fibrosis than proapoptotic, pro-inflammatory senescent cells and can even contribute to tissue repair (for example, through the growth factors VEGF-A and PDGF-AA)61,65.

노화가 진행되는 대부분의 세포는 

SASP를 생성합니다(그림 1). 

노화 세포의 30~70%에서 

이 SASP는 

염증 유발, 

세포 사멸 촉진 및 섬유화 촉진 인자를 수반하며7,31,40,59,60,61,62,63,64, 

이 중 일부는 내분비적 방식으로 

국소적으로나 원거리에서 이전에 노화되지 않았던 세포가 

노화되도록 만들 수 있습니다24,39,47. 

이러한 세포 사멸 촉진 SASP는 

노화 세포의 축적과 

지속성으로 인해 국소적 및 전신적으로 해로운 영향을 미칠 수 있습니다24. 

다른 30~70%의 노화 세포에서 SASP는 

성장 및 기타 재생 인자로 구성되는 것으로 보이며, 

잠재적으로 세포 사멸, 

조직 파괴 및 섬유화를 유발하는 세포 사멸성, 

염증성 노화 세포보다 덜 유발하며 

조직 복구에 기여할 수도 있습니다(예: 성장 인자 VEGF-A 및 PDGF-AA)61,65).

If senescent cells are present transiently, beneficial functions of both the proapoptotic and pro-growth types of SASP can orchestrate tissue remodeling (during fetal development, growth of younger individuals, and after cell or tissue damage), induce immune responses during infections or tissue injury, promote parturition by SASP factors released by placental senescent cells, and induce clearance of those senescent cells with a pro-inflammatory SASP because they attract, anchor and activate immune cells10,11,14,61,62,65.

노화 세포가 일시적으로 존재하는 경우, 

세포 자멸사 및 성장 촉진 유형의 SASP의 유익한 기능은 

조직 리모델링(태아 발달, 어린 개체의 성장, 세포 또는 조직 손상 후)을 조율하고, 

감염 또는 조직 손상 시 면역 반응을 유도하며, 

태반 노화 세포가 방출하는 SASP 인자에 의한 분만을 촉진하고, 

면역 세포를 유인, 고정 및 활성화하기 때문에 염

증성 SASP로 이러한 노화 세포의 제거를 유도할 수 있습니다10,11,14,61,62,65.

Adverse impacts of persistent, proapoptotic SASP-expressing senescent cells

Normally, senescent cells appear to be cleared within days to weeks after they develop by natural killer cells and other immune cell types62,66,67,68,69. However, if a threshold burden of senescent cells is exceeded, senescent cells can accumulate, perhaps because proapoptotic SASP-expressing senescent cells induce paracrine and endocrine spread of senescence at a rate exceeding immune clearance of preexisting and newly formed senescent cells24,62 (Fig. 2). Once senescent cell burden surpasses this threshold, continuing increases in proapoptotic/pro-inflammatory senescent cell burden may contribute to tissue destruction and hence development or progression of multiple diseases and age-related disorders (Table 2) as well as immune dysregulation, further amplifying senescent cell accumulation in a feed-forward loop36,38,62. Although not every senescent cell develops a proapoptotic, inflammatory SASP, accumulation and persistence of such senescent cells can induce a chronic low-grade, pro-fibrotic inflammatory state (usually associated with aging and chronic diseases), known as ‘inflammaging’70. This sterile inflammatory state can provoke dysfunction of neighboring and distant non-senescent cells, such as progenitor cells, contributing to impaired tissue function and reduced regenerative capacity18,21,24,26,34. Consistent with this, persistence of senescent cells has been implicated in causing disorders related to tissue inflammation, fibrosis and extracellular matrix degradation, adipose tissue insulin resistance, reduced muscle hypertrophy after resistance exercise and impaired fracture repair in older individuals, as well as promoting malignant transformation6,18,22,23,48,71,72,73,74,75,76,77.

일반적으로 노화 세포는 

자연 살해 세포 및 기타 면역 세포 유형62,66,67,68,69에 의해 

발생 후 수일에서 수주 내에 제거되는 것으로 보입니다. 

그러나 

노화 세포의 역치 부담을 초과하면 

노화 세포가 축적될 수 있는데, 

이는 아마도 세포 자멸사 SASP 발현 노화 세포가 

기존 및 새로 형성된 노화 세포의 면역 제거를 초과하는 속도로 

노화의 파라크린 및 내분비 확산을 유도하기 때문일 것입니다24,62 (그림 2). 

노화 세포 부담이 이 임계값을 초과하면 

세포 자멸사/염증성 노화 세포 부담이 지속적으로 증가하여 

조직 파괴와 여러 질병 및 노화 관련 장애의 발생 또는 진행에 기여할 수 있으며(표 2), 

면역 조절 장애를 일으켜 

피드포워드 루프에서 노화 세포 축적을 더욱 증폭시킬 수 있습니다36,38,62. 

모든 노화 세포가 

세포 자멸사, 

염증성 SASP를 일으키는 것은 아니지만, 

이러한 노화 세포의 축적과 지속은 

'염증'으로 알려진 만성 저등급의 섬유화성 염증 상태(일반적으로 노화 및 만성 질환과 관련이 있음)를 유발할 수 있습니다70. 

이러한 무균 염증 상태는 

전구 세포와 같은 인접 및 원거리 비감각 세포의 기능 장애를 유발하여 

조직 기능 손상과 재생 능력 감소에 기여할 수 있습니다18,21,24,26,34. 

이에 따라 노화 세포의 지속성은 

조직 염증, 

섬유화 및 세포 외 기질 분해, 

지방 조직 인슐린 저항성, 

저항성 운동 후 근육 비대 감소, 

고령자의 골절 회복 장애와 관련된 장애를 유발하고 

악성 변형을 촉진하는 것과 관련이 있습니다6,18,22,23,48,71,72,73,74,75,76,77.

Fig. 2: The threshold theory of senescent cell accumulation.

This theory postulates that once senescent cell burden exceeds a threshold, self-amplifying paracrine and endocrine spread of senescence through the SASP outpaces clearance of senescent cells by the immune system34,219. Additionally, increased abundance of SASP factors may impede immune system function62,78, further amplifying accumulation of senescent cells. Senescent cell accumulation may also accelerate other fundamental aging mechanisms. In studies of effects of transplanting senescent versus non-senescent cells into middle-aged mice, a minimum number of transplanted senescent cells was necessary to cause accelerated aging-like phenotypes24. In conditions in which senescent cell burden is already high, such as obesity, fewer senescent cells need to be transplanted to induce the same effect as in lean mice of the same age23,24,151. Consistent with this, in human childhood cancer survivors who have had DNA-damaging anticancer therapy, a subsequent accelerated aging-like phenotype can occur at a considerably earlier age than in older individuals who do not have a history of childhood cancer treatment169. Hence, senescent cells with a proapoptotic, inflammatory SASP may need to exceed a threshold to exert detrimental effects. Systemic clearance of senescent cells by genetic or pharmacologic means tends to attenuate the other pillars of aging and can delay, prevent or alleviate multiple age-related disorders and diseases23,24,30,49.

이 이론에 따르면 

노화 세포 부담이 임계치를 초과하면 

SASP를 통한 노화의 자가 증폭 파라크린 및 

내분비 확산이 면역계에 의한 

노화 세포 제거를 앞지른다고 가정합니다34,219. 

또한, SASP 인자의 증가는 

면역계 기능을 저해하여62,78 

노화 세포의 축적을 더욱 증폭시킬 수 있습니다. 

노화 세포 축적은 

다른 근본적인 노화 메커니즘을 

가속화할 수도 있습니다. 

노화 세포와 비노화 세포를 중년 쥐에 이식했을 때의 효과를 연구한 결과, 

노화와 유사한 표현형을 가속화하기 위해서는 

최소한의 노화 세포를 이식하는 것이 필요했습니다24. 

비만과 같이 

노화 세포의 부담이 이미 높은 상태에서는 

같은 연령의 마른 생쥐와 동일한 효과를 유도하기 위해 

더 적은 수의 노화 세포를 이식해야 합니다23,24,151. 

이와 일관되게, 

DNA를 손상시키는 항암 치료를 받은 인간 소아암 생존자의 경우 

소아암 치료 경험이 없는 고령자보다 

상당히 이른 나이에 노화와 유사한 표현형이 가속화될 수 있습니다169. 

따라서 

세포 자멸사, 

염증성 SASP를 가진 노화 세포는

 해로운 영향을 미치기 위해 임계치를 초과해야 할 수 있습니다. 

유전적 또는 약리학적인 방법으로 

노화 세포를 전신적으로 제거하면 

노화의 다른 기둥을 약화시키는 경향이 있으며 

여러 노화 관련 장애 및 질병을 지연, 예방 또는 완화할 수 있습니다23,24,30,49.

Table 2 Disorders and diseases linked to senescent cell accumulation and alleviated by senolytics in preclinical models

Full size table

The SASP of senescent cells is not static; it can change over time78,79,80 and varies depending on the type of cells that became senescent and how senescence was induced16,44,59,60,81. The intracellular and extracellular environment can modulate which SASP factors are produced and their abundance. Persistent senescent cells appear to be highly responsive to extracellular cues, such as damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), which can exacerbate the proapoptotic, pro-inflammatory qualities of the SASP16. For example, in the case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, some of these extracellular cues are mediated through Toll-like receptor 3 and angiotensin converting enzyme-2, contributing to coronavirus disease 2019 (COVID-19) morbidity44,82. Intracellular cues can exacerbate damaging, pro-inflammatory properties of the SASP several weeks or months after senescence has been induced. These include retrotransposable elements (for example, LINE-1), cytosolic mitochondrial DNA, or circular DNA—all of which can activate the cytosolic DNA-sensing (cGAS)–STING pathway, triggering the expression‎ of pro-inflammatory genes79,80,81.

노화 세포의 SASP는 

시간이 지남에 따라 변화할 수 있으며78,79,80, 

노화 세포의 유형과 노화가 어떻게 유도되었는지에 따라 달라집니다16,44,59,60,81. 

세포 내 및 세포 외 환경은 

생성되는 SASP 인자의 종류와 그 양을 조절할 수 있습니다. 

지속적인 노화 세포는 

손상 관련 분자 패턴(DAMP) 및 병

원체 관련 분자 패턴(PAMP)과 같은 세포 외 신호에 매우 민감하게 반응하는 것으로 보이며, 

이는 SASP16의 세포 자멸사, 염증 유발 특성을 악화시킬 수 있습니다. 

예를 들어, 

중증 급성 호흡기 증후군 코로나바이러스 2(SARS-CoV-2) 감염의 경우, 

이러한 세포 외 신호 중 일부는 

톨 유사 수용체 3과 안지오텐신 전환 효소-2를 통해 매개되어 

코로나바이러스 감염증 2019(COVID-19) 이환율에 기여합니다44,82. 

세포 내 단서는 

노화가 유도된 후 

몇 주 또는 몇 달 후에 SASP의 손상 및 염증 유발 특성을 악화시킬 수 있습니다. 

여기에는 

역전사 가능한 요소(예: LINE-1), 

세포질 미토콘드리아 DNA 또는 원형 DNA가 포함되며, 

이 모든 요소는 세포질 DNA 감지(cGAS)-STING 경로를 활성화하여 

염증성 유전자의 발현을 유발할 수 있습니다79,80,81.

Discovery and development of senolytic drugs

The first senolytic drugs were identified using a hypothesis-driven, mechanism-based drug discovery approach (Fig. 3). Because those 30–70% of senescent cells that have a proapoptotic, tissue-destructive SASP are themselves resistant to apoptosis, it was hypothesized that such senescent cells depend on antiapoptotic, pro-survival pathways to avoid self-destruction14,83. Analysis of proteomic and transcriptomic datasets revealed there is indeed upregulation of one or more senescent cell antiapoptotic pathways (SCAPs) in senescent cells. SCAP pathways are similar to those that protect certain types of cancer cells, such as B cell lymphoma or chronic lymphocytic leukemia cells, which also release tissue-destructive proapoptotic factors but evade undergoing apoptosis themselves84,85. Transiently disabling SCAP pathways results in apoptosis of the senescent cells with a tissue-destructive SASP, while non-senescent cells or those senescent cells with a pro-growth, non-apoptotic SASP remain viable (U. Tripathi, S.C., L.G.P.L. Prata, T.T. and J.L.K., unpublished data).

최초의 세포 분해 약물은 

가설 중심의 메커니즘 기반 약물 발견 접근법을 사용하여 확인되었습니다(그림 3). 

세포사멸을 촉진하고 

조직을 파괴하는 SASP를 가진 노화 세포의 30~70%는 

그 자체로 세포사멸에 저항성이 있기 때문에, 

이러한 노화 세포는 자가 파괴를 피하기 위해 

항세포사멸, 친생존 경로에 의존한다는 가설이 세워졌습니다14,83. 

단백질체 및 전사체 데이터 세트를 분석한 결과, 

실제로 노화 세포에서 

하나 이상의 노화 세포 항세포사멸 경로(SCAP)가 

상향 조절된다는 사실이 밝혀졌습니다. 

SCAP 경로는 

조직 파괴적인 전세포 사멸 인자를 방출하지만 

세포 사멸 자체를 회피하는 

B세포 림프종이나 만성 림프구성 백혈병 세포와 같은 

특정 유형의 암세포를 보호하는 경로와 유사합니다84,85. 

SCAP 경로를 일시적으로 비활성화하면 

조직 파괴적인 SASP를 가진 노화 세포는 

세포 사멸이 일어나지만, 

비노화 세포 또는 성장 촉진적이고 

세포 사멸이 일어나지 않는 SASP를 가진 노화 세포는 

생존할 수 있습니다(U. Tripathi, S.C., L.G.P.L. Prata, T.T. 및 J.L.K., 미공개 데이터).

Fig. 3: First- and second-generation senolytic strategies.

First-generation senolytics target different SCAPs, including tyrosine kinase receptors (TKRs), growth factor receptors (GFRs), ephrin receptor B1 (EFNB1), SRC kinases, PI3K–AKT, HSP90, BCL-2 family members, caspase inhibition and p53 modulation14,54,57,86,87,88. High-throughput library screens and other approaches have informed second-generation senolytic strategies, including lysosomal and SA-β-gal-activated prodrugs and nanoparticles54,92,93,220, sodium–potassium pump (Na+/K+-ATPase)-dependent apoptosis194,221, SASP inhibition103,104,105,106 and immune-mediated clearance by CAR T cells, antibody–drug conjugates or vaccines62,96,97,98,99.

1세대 세놀리틱스는 

티로신 키나아제 수용체(TKR), 

성장인자 수용체(GFR), 

에프린 수용체 B1(EFNB1), 

SRC 키나아제, 

PI3K-AKT, 

HSP90, BCL-2 계열, 

카스파제 억제 및 p53 변조14,54,57,86,87,88 등 

다양한 SCAP를 표적으로 삼습니다. 

고처리량 라이브러리 스크린 및 기타 접근법은 

리소좀 및 SA-β-gal 활성화 전구체 및 나노입자54,92,93,220, 

나트륨-칼륨 펌프(Na+/K+-ATPase) 의존성 세포사멸194,221, 

SASP 억제103,104,105,106 및 CAR T 세포, 

항체-약물 접합체 또는 

백신에 의한 면역 매개 제거62,96,97,98,99를 포함한 

2세대 세노시스 전략에 정보를 제공했습니다.

Bioinformatic analyses identified 46 compounds that target SCAP pathways as being potentially senolytic14. The first senolytic agents intentionally selected for further investigation were ones that: (1) target several SCAPs, rather than adhering to the traditional drug development approach of one drug/one molecular target/one disease, (2) can be administered orally, and (3) are natural products with known safety profiles or are already approved by the US Food and Drug Administration (FDA) for other indications, to facilitate translation from bench to bedside. These included the SRC/tyrosine kinase inhibitor dasatinib (D), which has been approved and extensively used since 2006 and has a quite good safety profile, and the natural flavonoids quercetin (Q) and fisetin (F), which are present in fruits and other foods14,86.

생물정보학적 분석 결과, 

SCAP 경로를 표적으로 하는 46개의 화합물이 

잠재적으로 노인성 질환을 유발할 수 있는 것으로 확인되었습니다14. 

추가 연구를 위해 의도적으로 선택한 첫 번째 노인성 물질은 다음과 같은 특징을 가진 물질이었습니다: 

(1) 하나의 약물/하나의 분자 표적/하나의 질병이라는 전통적인 약물 개발 접근법을 고수하지 않고 여러 SCAP를 표적으로 하며, 

(2) 경구 투여가 가능하고, 

(3) 안전성 프로파일이 알려진 천연물이거나 다른 적응증에 대해 이미 미국 식품의약국(FDA)의 승인을 받아 연구실에서 병상까지 쉽게 이동할 수 있는 약물이었습니다. 

여기에는 2006년부터 승인되어 광범위하게 사용되고 있으며 

안전성 프로파일이 상당히 우수한 

SRC/티로신 키나아제 억제제 다사티닙(D)과 

과일 및 기타 식품에 존재하는 천연 플라보노이드 케르세틴(Q) 및 피세틴(F)이 포함됩니다14,86.

In some types of senescent cells, SCAPs can be redundant, so that targeting a single SCAP may not eliminate such cells—but combination treatment targeting multiple SCAPS may be effective. As an example, senescent mesenchymal embryonic fibroblasts from Ercc1−/− mice and bone marrow mesenchymal progenitors from old mice are not eliminated by either D or Q alone, but are eliminated by the combination of these agents14. Consistent with the heterogeneity of SCAPs across different senescent cell types, senescent human fat cell progenitors (preadipocytes or mesenchymal stromal cells) are sensitive to D but not Q or F, while senescent human umbilical vein endothelial cells are sensitive to Q or F but not D14. Since the first SCAPs were discovered, others have been identified and, based on these, more senolytic strategies have been developed. For example, forkhead box O4 (FOXO4) retains p53 in the nucleus, so peptides interfering with this interaction can lead to p53-mediated apoptosis in some types of senescent cells87. HSP90 prevents proteasomal degradation of AKT, hence inhibiting HSP90 disables pro-survival signaling through this SCAP node and results in elimination of some senescent cell types54.

일부 유형의 노화 세포에서는

 SCAP이 중복될 수 있으므로 

단일 SCAP을 표적으로 삼아도 

해당 세포가 제거되지 않을 수 있지만, 

여러 SCAP을 표적으로 하는 병용 치료는 효과적일 수 있습니다. 

예를 들어, Ercc1-/- 마우스의 노화 중간엽 배아 섬유아세포와 늙은 마우스의 골수 중간엽 전구세포는 D 또는 Q 단독으로는 제거되지 않지만, 이들 약제를 병용하면 제거됩니다14. 

다양한 노화 세포 유형에 걸친 SCAP의 이질성과 일관되게, 

노화 인간 지방 세포 전구세포(전지방세포 또는 간엽 기질 세포)는 D에 민감하지만 Q나 F에는 민감하지 않은 반면, 노화 인간 제대 정맥 내피 세포는 Q나 F에는 민감하지만 D에는 민감하지 않습니다14. 

최초의 SCAP이 발견된 이후 다른 SCAP이 발견되었고, 

이를 바탕으로 더 많은 노화 억제 전략이 개발되었습니다. 

예를 들어, 포크헤드 박스 O4(FOXO4)는 핵에 p53을 보유하므로 이 상호 작용을 방해하는 펩타이드는 일부 유형의 노화 세포에서 p53 매개 세포 사멸을 유발할 수 있습니다87. HSP90은 AKT의 프로테아좀 분해를 방지하므로 HSP90을 억제하면 이 SCAP 노드를 통한 친생존 신호가 무력화되어 일부 노화 세포 유형이 제거됩니다54.

Consistent with this, certain HSP90 inhibiting drugs, such as geldanamycin, are senolytic against particular senescent cell types.

In some cases, senolytic compounds that target a single SCAP node, such as the BCL-2 pathway inhibitors, N (ABT-263), A1331852 or A1155463, tend to induce apoptosis in a restricted range of senescent cell types57,86. However, it is worth noting that N can cause thrombocytopenia and neutropenia, even after brief exposures57,88,89,90,91; this raises the question of whether agents that target a single molecular pathway have a greater risk of toxicity due to off-target effects associated with the high dosing required to fully suppress a single SCAP node. Perhaps by using agents or combinations that ‘lightly’ impact a number of nodes, it may be feasible to target a broader range of senescent cell types while using lower doses of each agent, thereby potentially improving the side-effect profiles of these agents. The latter approach has been used to improve tolerability of antibiotic treatments, for example.

이와 일관되게, 겔다나마이신과 같은 특정 HSP90 억제 약물은 특정 노화 세포 유형에 대해 세포 분해 작용을 합니다.

경우에 따라 

BCL-2 경로 억제제인 N(ABT-263), A1331852 또는 

A1155463과 같이 단일 SCAP 노드를 표적으로 하는 세포 사멸 화합물은 

제한된 범위의 노화 세포 유형57,86에서 

세포 사멸을 유도하는 경향이 있습니다. 

그러나 

N은 짧은 노출 후에도 혈소판 감소증과 호중구 감소증을 유발할 수 있다는 

점에 주목할 필요가 있습니다57,88,89,90,91; 

이는 단일 분자 경로를 표적으로 하는 약제가 

단일 SCAP 노드를 완전히 억제하는 데 필요한 

고용량 투여와 관련된 표적 외 효과로 인해 

독성 위험이 더 큰지에 대한 의문을 제기합니다. 

여러 노드에 '가볍게' 영향을 미치는 약제 또는 조합을 사용하면 각 약제의 용량을 줄이면서 더 광범위한 노화 세포 유형을 표적으로 삼을 수 있어 잠재적으로 이러한 약제의 부작용 프로필을 개선할 수 있을 것입니다. 예를 들어, 후자의 접근 방식은 항생제 치료의 내약성을 개선하는 데 사용되었습니다.

Second-generation senolytics are now being identified using high-throughput library screens and other approaches54. One approach stems from the increase in lysosomal mass and senescence-associated β-galactosidase activity in many senescent cells, whereby galacto-oligosaccharide-coated nanoparticles and β-galactosidase-activated prodrugs appear to eliminate at least some of these cells92,93. Another approach is based on the high lysosomal activity of some senescent cells that renders them sensitive to lysosomal ATPase inhibitors94. Due to ruptured lysosomal membranes, at least some senescent cells depend on glutamine metabolism as a pH-buffering system, inhibition of which renders them vulnerable to apoptosis95.

Other strategies for decreasing age-related senescent cell burden and pathologic conditions involve modulating immune clearance of senescent cells62. Certain cell surface proteins tend to be more highly expressed by senescent cells than most other cell types, which prompted development of engineered chimeric antigen receptor (CAR) T cells, vaccines and antibody–drug conjugates targeting these cell surface markers. Each of these approaches eliminates senescent cells, although in some cases, activated macrophages and other non-senescent cell types are also affected96,97,98,99. It is not yet clear if these approaches eliminate primarily those senescent cells with a proapoptotic, inflammatory, tissue-destructive SASP, those with a mainly growth-promoting SASP, or both forms of senescent cells. A possible advantage of small-molecule senolytics over vaccines or transplanted CAR T cells is that if a need for senescent cells occurs, for example, during wound healing, tissue remodeling or pregnancy, then treatment can be discontinued—whereas the continued elimination of senescent cells induced by vaccines or CAR T strategies may not readily be switched off. Furthermore, CAR T cell therapy is expensive, generally has to be specifically formulated for each individual being treated, and can lead to graft versus host disease, necessitating prolonged immunosuppressive therapy with all its attendant risks.

It should be noted that in commonly used preclinical models, senescence is abolished by means of p16INK4a-based or p21CIP1/WAF1-based genetic clearance and this senescence-targeting approach acts through mechanisms that are distinct from first-generation, SCAP-targeting small-molecule senolytics; as a result, there appear to be differences in the types of senescent cells targeted. For example, cell types such as activated macrophages, which may not be classically senescent, can have high p16INK4a expression‎100, but are not targeted by D + Q24. Unpublished work from our own laboratory suggests that there may be differences in the phenotypic effects (such as those relating to wound healing and healthspan) of targeting senescent cells in transgenic mice compared to the effects of senolytic agents in wild-type mice. This is in agreement with a recent report showing that the removal of senescent cells expressing high levels of p16INK4a can lead to fibrosis in mice101, whereas small-molecule senolytics appear to reduce fibrosis in several mouse tissues22,71,73,75,102. Indeed, work to develop senolytics began before genetic models of senescent cell clearance were published and did not depend on those models34,56. These genetic models have been useful in pinpointing those cells expressing particular senescence-linked markers (for example, p16INK4a or p21CIP1/WAF1) and as complementary tools in senolytic proof-of-concept studies (Table 2). However, given their inability to eliminate the naturally occurring heterogeneous senescent cell pool (that is, elimination of both p16INK4a-expressing or p21CIP1/WAF1-expressing cells or senescent cells that express neither) and the fact that also non-senescent cells such as activated macrophages are targeted100, these genetic models are of limited use to assess the translational potential of senolytic agents—but are useful for mechanistic insights nonetheless.

SASP inhibitors

Suppressing the SASP without eliminating senescent cells is an alternative therapeutic approach for alleviating cellular senescence-related phenotypes or diseases. SASP inhibitors (senomorphics) can directly or indirectly attenuate the SASP of senescent cells by inhibiting transcription factor nuclear factor (NF)-κB, the JAK–STAT signal transduction pathway, the serine/threonine protein kinase mTOR, mitochondrial complex-1-related or 4-related targets, or other pathways involved in the induction and maintenance of the SASP103,104,105,106. In vitro and in vivo, inhibitors of NF-κB (mediating the cell response to inflammation), can reduce pro-inflammatory SASP cytokines and chemokines104. In addition, an RNA-mediated interference screen revealed that targeting alternative splicing in senescent cells may be a viable approach for inhibiting the SASP107. Rapamycin and its analogs (so-called ‘rapalogs’) suppress the SASP by inhibiting mTOR and appear to extend healthspan and lifespan in mice105,108,109. The antidiabetic drug metformin, which, among other activities, inhibits the SASP, alleviates several age-related conditions and chronic diseases110,111,112,113,114. A clinical trial (TAME, Targeting Aging with Metformin) is planned to test if metformin delays the time for a second age-related disease to occur in patients who already have a single age-related condition115.

Advantages and disadvantages of senolytics versus SASP inhibitors

There are important differences between SASP inhibitors and senolytics. Whereas SASP inhibitors potentially suppress both the growth-promoting as well as the proapoptotic, inflammatory, tissue-destructive sets of SASP factors, the first-generation senolytics target the underlying cause of detrimental SASP factor production by eliminating those senescent cells that release proapoptotic factors. In the case of SASP inhibitors, continuous treatment is needed to maintain suppression of the SASP, although some agents, such as rapamycin, can have prolonged effects after a brief course of administration116,117. This may be a result of inhibiting SASP-mediated spread of senescence, thereby allowing the innate and adaptive immune system to further reduce senescent cell burden, consistent with the Unitary Theory (Fig. 2). With senolytics, intermittent administration appears to be as effective as continuous treatment for attenuating senescent cell burden21. This intermittent ‘hit-and-run’ strategy of senolytic administration could serve to reduce side effects of agents such as D, which generally appear after weeks to months of continuous administration118,119. In this regard, the advantages of D, Q or F over some other senolytics are their brief half-lives (4, 11 or 3–4 h, respectively, in humans) and rapid elimination120,121,122. The greater need for continuous administration of SASP inhibitors could lead to more side effects than seen with intermittently dosed senolytics and could also lead to off-target effects due to suppression of cytokine secretion—even when such cytokines are needed—by non-senescent cells such as innate or adaptive immune cells. Furthermore, some SASP inhibitors can have agent-specific off-target effects, for example, rapamycin, which can cause nephrotoxicity, metabolic impairment and susceptibility to infections, at least at higher doses in mice109.

Senolytics cause SASP-expressing senescent cells to undergo apoptosis, and such senescent cells are present at sites of dysfunction. Interestingly, a study involving transplanted mesenchymal stromal cells, which have therapeutic effects in a wide range of disease models, may hint at a possible mechanism for the beneficial effects of senolytic-induced apoptosis. The study suggested that apoptosis of mesenchymal stromal cells is required for their therapeutic effects, possibly by means of downstream immunosuppressive effects of apoptotic processes123. This raises the intriguing hypothesis that senolytic-induced apoptosis of destructive SASP-expressing senescent cells, which are concentrated at sites of pathology, might contribute to the beneficial effects of senolytics, which has not been directly tested in preclinical models in currently available reports.

Consideration of the different cell populations affected by senolytic and SASP inhibitor interventions, whether expressing a detrimental tissue-destructive or beneficial pro-growth factor secretory phenotype, is crucial to the successful development of senotherapeutic interventions61. Elimination of all senescent cells or general inhibition of the SASP might be detrimental in some instances in which senescent cells are beneficial. However, interventions that predominantly target the persisting, tissue-destructive SASP-expressing senescent cells might have superior therapeutic potential and fewer off-target effects.

Senolytics in preclinical models

First-generation senolytics, such as D + Q, have been tested in several preclinical models of aging and diseases, including type 2 diabetes, and bone, heart, kidney, liver, lung, muscle and neurological disorders (Table 2). Whereas transplanting senescent cells decreases healthspan and lifespan in preclinical models, eliminating transplanted or endogenous senescent cells increases healthspan, thereby fulfilling Koch’s postulates for causality24,124.

In mouse models of diet-induced obesity, reducing the burden of senescent cells in adipose tissue by administering D + Q attenuates adipose tissue inflammation, alleviates metabolic dysfunction, and restores the capacity of preadipocytes to differentiate into functional, mature, insulin-responsive fat cells25. High-fat diets (HFDs) and obesity result in senescent cell accumulation and lead to impaired function of multiple organs. For example, HFD-induced senescent mouse kidney cells are linked to renal fibrosis and functional impairment; Q treatment reduces senescent cell burden and SASP marker expression‎, alleviates renal fibrosis and improves kidney function102. In livers of HFD-fed mice, oral D + Q reduces the burden of senescent hepatocytes and hepatic steatosis75. Obesity also leads to accumulation of senescent cells near the third ventricles of the murine brain, together with development of neuropsychiatric dysfunction, particularly anxiety, which results from altered function of the limbic system situated near the third ventricles. Oral D + Q reduces this neuroinflammation, increases markers of neurogenesis, reduces gliosis and alleviates anxiety in obese mice33. Fibrosis can be a senescence-driven progressive process that contributes to reduced organ function; in a mouse model of idiopathic pulmonary fibrosis (IPF), D + Q treatment improved lung compliance and reduced frailty71. In age-related osteoporosis linked to senescent-like osteocytes and bone marrow cells in mice, D + Q reduced development of bone-resorbing osteoclasts, while increasing differentiated bone-forming osteoblasts, with restoration of bone mass21. After resistance exercise, senescent cells develop in muscle of old mice in tandem with impaired exercise-induced muscle hypertrophy compared to young mice18. D + Q alleviates this negative impact of aging on muscle growth. Recently, senescent cells have been implicated in accentuating the severity of viral infections due to amplification of SASP factor secretion, predisposing to cytokine storm and multi-organ failure. In mice infected with a murine coronavirus, the mortality rate was reduced following administration of D + Q or F16.

Transplanted senescent cells or organs from old mice have been shown to spread the senescent phenotype to distant sites in recipient mice, predisposing to detrimental outcomes after transplantation24,31. D + Q treatment of either old donor mice, the organs harvested from the old donors before transplantation, or the recipients, led to decreased senescent cell burden and increased survival of recipient mice – so that outcomes resembled those observed in mice receiving a transplant from a young donor31. Hence, a potential new application of senolytics may entail ex vivo perfusion of organs from older donors that are currently being discarded because of increased risk of organ failure or allograft rejection, potentially offsetting shortages of organs for transplantation125.

A recent study implicated cellular senescence and the beneficial effects of senolytics for Down syndrome (trisomy 21)13. A third copy of chromosome 21 in neural progenitor cells leads to transcriptional and nuclear organizational changes similar to those in senescent cells. Interestingly, D + Q alleviated transcriptional changes and cellular dysfunction in an in vitro human neural cell Down syndrome model. An accelerated aging-like phenotype has been observed in astronauts who are exposed to radiation, high G-forces, zero gravity and cabin air quality126. Thus, senolytics might support long-distance space exploration by eliminating the senescent cells caused by cosmic and solar radiation, especially outside the van Allen radiation belts. In April 2022, effects of space travel on senescence biomarkers in astronauts and cultured human fat cell progenitors were tested during the Axiom-1 mission to the International Space Station; data are pending127.

Systemic versus local administration

According to the threshold theory of cellular senescence, senescent cells can be present without clinical manifestations but, if their abundance exceeds a threshold, senescent cell burden can increase further and contribute to development of local and systemic dysfunction and multiple diseases (Fig. 2). Senescent cells can spread even to distant sites because of their SASP; therefore, systemic, intermittent administration of senolytics for senescence-associated diseases is potentially more promising than local administration, with the exception of perhaps eye, skin or dental topical or other local applications34. Perhaps there may not need to be strict cell type specificity of senolytics administered in vivo. Arguably, once systemic senolytic treatment has reduced overall senescent cell burden to below a threshold, the immune system might clear remaining senescent cells, including those resistant to that particular senolytic. This could be especially important for older individuals or those with chronic diseases, who already have a high systemic senescent cell burden24,128. Strategies for systemic senolytic administration include oral or intravenous routes, with orally active senolytics generally being more accepted by patients and less expensive to administer. The timing, the particular senolytic agent used, and the age, sex, and other characteristics of the individual may impact effectiveness of senolytics24. For example, F may be beneficial but D detrimental in healthy young female mice that have not yet accumulated many senescent cells129.

세포 노화의 역치 이론에 따르면 

노화 세포는 임상 증상 없이 존재할 수 있지만, 

그 양이 역치를 초과하면 

노화 세포 부담이 더욱 증가하여 

국소 및 전신 기능 장애와 여러 질병의 발병에 기여할 수 있습니다(그림 2). 

노화 세포는 

SASP로 인해 먼 부위까지 퍼질 수 있으므로 

노화 관련 질환에 대한 노화 억제제를 전신적으로 간헐적으로 투여하는 것이 

눈, 피부 또는 치아 국소 또는 기타 국소 적용을 제외하고는 국소 투여보다 잠재적으로 더 유망할 수 있습니다34. 

아마도 생체 내에서 투여되는 노화억제제의 세포 유형 특이성이 엄격할 필요가 없을 수도 있습니다. 

전신적인 세포 분해제 치료를 통해 전

반적인 노화 세포의 부담이 임계치 이하로 줄어들면 

면역 체계가 특정 세포 분해제에 내성을 가진 세포를 포함하여 

남아있는 노화 세포를 제거할 수 있을 것입니다. 

이는 

이미 전신 노화 세포 부담이 높은 고령자나 

만성 질환을 앓고 있는 사람들에게 

특히 중요할 수 있습니다24,128. 

전신 노화 세포 용해제 투여 전략에는 

경구 또는 정맥 투여가 포함되며, 

일반적으로 경구 활성 노화 세포 용해제가 

환자에게 더 잘 받아들여지고 투여 비용도 저렴합니다. 

투여 시기, 

사용되는 특정 노인성 질환 치료제, 

개인의 연령, 

성별 및 기타 특성은 

노인성 질환 치료제의 효과에 영향을 미칠 수 있습니다24. 

예를 들어, 아직 노화 세포가 많이 축적되지 않은 건강한 젊은 암컷 생쥐의 경우 F는 유익할 수 있지만 D는 해로울 수 있습니다129.

Clinical trials and future directions

Based on promising results in preclinical models, over 20 clinical trials of senolytic therapies are completed, ongoing or planned34 (Table 1). Because side effects of senolytics in humans are not yet fully known, and to maximize benefit–risk ratios, the first clinical trials are underway in patients with serious health conditions, such as diabetic kidney disease, Alzheimer’s disease, frailty and IPF34. The first in-human trial of senolytics (D + Q), the Hematopoietic Stem Cell Transplant Survivors Study, is still underway (NCT02652052; first patient dosed on 1 April 2016). The first senolytic clinical trial published was an open-label pilot study in which 14 patients with IPF were treated with intermittent D + Q on 3 d per week for 3 weeks63. Results suggested that senolytics improved physical function in these frail patients. Furthermore, post hoc analysis of a study involving 20 patients with IPF showed that urine levels of the ‘geroprotective’ factor α-Klotho were higher after oral D + Q than before treatment19. In an open-label phase 1 pilot study in 9 patients with diabetic kidney disease, a 3-d course of oral D + Q was sufficient to decrease adipose tissue senescent cell burden, inflammation, fibrosis and circulating SASP factors for at least 11 d after the last dose of senolytics, indicating target engagement and suggesting that an intermittent dosing regimen may be effective in humans48. These early data warrant eval‎uation in larger randomized, double-blind, placebo-controlled trials for senescence-associated disorders and diseases, some of which are underway34 (Table 1).

전임상 모델의 유망한 결과를 바탕으로 20개 이상의 노인성 질환 치료법 임상시험이 완료되었거나 진행 중이거나 계획 중입니다34(표 1). 

인간에 대한 세놀리제의 부작용은 

아직 완전히 알려지지 않았고, 

유익성 대비 위험성을 극대화하기 위해 

당뇨병성 신장 질환, 

알츠하이머병, 

허약,

 IPF와 같은 심각한 건강 상태를 가진 환자를 대상으로 

첫 번째 임상시험이 진행 중입니다34. 

조혈모세포 이식 생존자 연구인 세놀리틱스(D + Q)의 첫 번째 인체 대상 임상시험이 진행 중입니다(NCT02652052, 2016년 4월 1일 첫 번째 환자 투약). 최초로 발표된 세놀리틱스 임상시험은 오픈 라벨 파일럿 연구로, 14명의 특발성폐섬유증 환자를 대상으로 3주 동안 주 3일 간헐적으로 D + Q를 투여했습니다63. 

연구 결과, 

세놀리틱스가 

허약한 환자들의 신체 기능을 개선하는 것으로 나타났습니다. 

또한, IPF 환자 20명을 대상으로 한 연구의 사후 분석 결과, 

경구용 D + Q를 복용한 후 

'노화 방지' 인자인 α-Klotho의 소변 수치가 치료 전보다 더 높은 것으로 나타났습니다19. 

당뇨병성 신장 질환 환자 9명을 대상으로 한 오픈라벨 1상 파일럿 연구에서 경구용 D + Q를 3일간 투여한 결과, 마지막 세놀제 투여 후 최소 11일 동안 지방 조직 노화 세포 부담, 염증, 섬유화 및 순환 SASP 인자를 감소시키는 데 충분했으며, 이는 표적 관여를 나타내며 간헐적 투여 요법이 인간에게 효과적일 수 있음을 시사합니다48. 이러한 초기 데이터는 노화 관련 장애 및 질병에 대한 대규모 무작위 이중맹검 위약 대조 임상시험에서 평가할 필요가 있으며, 현재 일부 임상시험이 진행 중입니다34(표 1).

It should be noted that a phase 2, randomized, double-blind, placebo-controlled clinical trial (NCT04349956)—in which the senolytic agent was a p53-destabilizing protein MDM2 inhibitor, UBX0101 (also known as nutlin-3a)—did not achieve its primary endpoint of improving pain in patients with osteoarthritis of the knee in a 12-week follow-up. In our hands and others, nutlin-3a does not show or shows only weak senolytic activity and, in some cases, can even induce cellular senescence95,130. Furthermore, in a mouse model of osteoarthritis, a combination of UBX0101 with N was necessary to restore aged joint structure131. Thus, the failure of this clinical trial seems related to the particular agent administered, which may not have been a fully effective senolytic.

노화 억제제가 

p53 불안정 단백질 MDM2 억제제인 UBX0101(nutlin-3a라고도 함)인 2

상 무작위 이중 맹검 위약 대조 임상 시험(NCT04349956)은 

12주 추적 관찰에서 무릎 골관절염 환자의 통증 개선이라는 

1차 평가 변수를 달성하지 못했다는 점에 유의할 필요가 있습니다. 

뉴트린-3a는 

노화 억제 효과가 없거나 약하게 나타났으며, 

경우에 따라서는 세포 노화를 유도할 수도 있습니다95,130. 

또한, 골관절염 마우스 모델에서 노화된 관절 구조를 회복하기 위해서는 UBX0101과 N의 조합이 필요했습니다131. 따라서 이 임상시험의 실패는 투여된 특정 약제와 관련이 있는 것으로 보이며, 이는 완전히 효과적인 노화 억제제가 아니었을 수 있습니다.

Biomarkers of senescent cell burden and senolysis: gerodiagnostics

Identification and monitoring of senescent cell burden in situ, especially during clinical trials to assess safety and efficacy, can be challenging if solely based on analysis of tissue biopsies given the contextual and complex regulation of the senescent cell fate. However, SASP factors, senescence markers and markers of other fundamental aging processes (for example, α-Klotho) can be assayed in body fluids such as urine, saliva, blood or cerebrospinal fluid7,19,48,59,61,64,132,133. Additionally, ongoing efforts are underway to identify and define biomarkers of senescent cell accumulation (senescence biomarkers) and destruction of senescent cells during senolytic treatment (senolysis biomarkers) that meet requirements of regulatory authorities. Panels of SASP factors and senolysis markers for clinical trials and, ultimately, clinical practice will be important as diagnostics/predictors for multiple disorders and diseases, monitoring target engagement and individualizing senolytic regimens for patients. Indeed, to facilitate developing interventions targeting fundamental aging processes and for eventual use in clinical practice, such indicators will need to be more than mere ‘biological clocks’. Indicators are needed that are reproducible, reliable, feasible and inexpensive to measure, and reflect not only biological age, but also correlate with clinical function and/or disabilities. These should also change in response to interventions, predict or reflect changes in clinical function caused by these interventions, and indicate which senolytic or SASP inhibitor may be best for an individual. Such biomarkers or composite scores of biomarkers are known as ‘gerodiagnostics’. Indeed, the first gerodiagnostic score sensitive to senolytic administration in humans was a blood composite score published in 2019 (ref. 48).

노화 세포의 운명에 대한 맥락적이고 복잡한 조절을 고려할 때, 

특히 안전성과 효능을 평가하기 위한 임상시험에서 

조직 생검 분석에만 의존할 경우 현장에서 노화 세포 부담을 식별하고 모니터링하는 것이 어려울 수 있습니다. 

그러나 

소변, 

타액, 

혈액 또는 

뇌척수액과 같은 체액에서 

SASP 인자, 노화 마커 및 기타 근본적인 노화 과정의 마커(예: α-Klotho)를 분석할 수 있습니다7,19,48,59,61,64,132,133. 

또한, 규제 당국의 요건을 충족하는 노화 세포 축적(노화 바이오마커) 및 노화 치료 중 노화 세포 파괴(노화 분해 바이오마커)의 바이오마커를 식별하고 정의하기 위한 노력이 계속되고 있습니다. 

임상시험과 궁극적으로 임상에서 다양한 장애와 질병의 진단/예측, 표적 관여 모니터링, 환자 개별 맞춤형 세포분해 요법 등을 위해 SASP 인자 및 세포분해 마커 패널이 중요해질 것입니다. 

실제로 근본적인 노화 과정을 목표로 하는 개입을 개발하고 궁극적으로 임상에서 사용하려면 이러한 지표가 단순한 '생물학적 시계' 그 이상이어야 합니다. 생물학적 나이뿐만 아니라 임상적 기능 및/또는 장애와의 상관관계를 반영하고, 재현 가능하고, 신뢰할 수 있으며, 측정이 가능하고, 저렴한 지표가 필요합니다. 또한 이러한 지표는 개입에 대한 반응으로 변화하고, 이러한 개입으로 인한 임상 기능의 변화를 예측하거나 반영하며, 개인에게 가장 적합한 노인성 질환 또는 SASP 억제제를 알려줄 수 있어야 합니다. 이러한 바이오마커 또는 바이오마커의 복합 점수를 '제로진단'이라고 합니다. 실제로, 인간을 대상으로 한 최초의 노인성 질환 진단 점수는 2019년에 발표된 혈액 복합 점수입니다(참조 48).

Additionally, we propose the concept of ‘gerodiagnostic ratios’, whereby gerodiagnostic indicators that increase with aging or disorders linked to acceleration of fundamental aging mechanisms, could be summed into a composite in the numerator (for example, markers of senescent cells, SASP factors, CD38 and mTOR activity indicators), while beneficial geroprotective factors (for example, α-Klotho or perhaps nicotinamide adenine dinucleotide (NAD+) or Sirt-6) could be in the denominator. This approach could both enhance sensitivity and reduce ‘denominator effects’; for example, creatinine is often used as a dominator for urine analytes, introducing the confounding variable of muscle mass, upon which creatinine levels depend.

또한, 노화 또는 근본적인 노화 메커니즘의 가속화와 관련된 장애와 함께 증가하는 노화 진단 지표(예: 노화 세포의 마커, SASP 인자, CD38 및 mTOR 활성 지표)를 분자에, 유익한 노화 보호 인자(예: α-Klotho 또는 니코틴아마이드 아데닌 디뉴클레오티드(NAD+) 또는 Sirt-6)를 분모에 포함하는 '노화 진단 비율' 개념을 제안합니다. 예를 들어, 크레아티닌은 종종 소변 분석의 분모로 사용되어 크레아티닌 수치에 의존하는 근육량이라는 혼란스러운 변수를 도입하는 경우가 많습니다.

Clinical trajectory for the next decade

Large, randomized controlled trials to assess and ensure safety, benefit and target engagement of senolytics are needed to validate preliminary results from early-phase clinical trials (Table 1). If safety and effectiveness of senolytics are first demonstrated in patients with serious diseases for which current treatments are inadequate, it could become acceptable to test them for less severe senescence-linked disorders. If safe and effective for such conditions, senolytics might then be tested for prevention of age-related dysfunction and diseases in older individuals, using a strategy like that which is planned for metformin in the TAME study115. TAME will test if metformin delays the appearance of a second age-related disorder in patients who already have one such disorder; it will not be a trial including completely healthy older adults115. If attempts to extend human healthspan are effective, future studies might conceivably aim to eval‎uate the role of senolytic therapies in extending human lifespan.

초기 단계 임상시험의 예비 결과를 검증하기 위해서는 

세놀라아제의 안전성, 

혜택 및 표적 관여도를 평가하고 보장하기 위한 

대규모 무작위 대조 임상시험이 필요합니다(표 1). 

현재 치료법이 불충분한 중증 질환을 앓고 있는 환자를 대상으로 

세놀라약의 안전성과 효과가 먼저 입증되면, 

덜 심각한 노화 관련 질환에 대해 세놀라약을 시험하는 것이 허용될 수 있을 것입니다. 

이러한 질환에 안전하고 효과적이라면, 노화 관련 기능 장애 및 질병 예방을 위해 TAME 연구에서 메트포르민에 대해 계획된 것과 같은 전략을 사용하여 노년층의 노화 관련 기능 장애 및 질병 예방을 위해 노화 방지제를 테스트할 수 있습니다115. TAME은 이미 한 가지 노화 관련 장애가 있는 환자에서 메트포르민이 두 번째 노화 관련 장애의 출현을 지연시키는지 테스트할 예정이며, 완전히 건강한 노인을 대상으로 하는 임상시험은 아닙니다115. 인간의 건강 수명을 연장하려는 시도가 효과적이라면, 향후 연구에서는 노화 방지 요법이 인간의 수명을 연장하는 데 어떤 역할을 하는지 평가하는 것을 목표로 할 수 있을 것입니다.

Combination therapeutic strategies

Clinical studies of geroscience interventions targeting the other pillars of aging are currently underway or being planned. Dietary interventions, such as caloric restriction and intermittent fasting, might be protective against development of age-related dysfunction and diseases based on studies in animal models134,135. Exercise may delay senescent cell formation and reduce inflammation, frailty and chronic disease onset in mice136,137. Metformin, resveratrol and rapalogs (agents related to rapamycin) are SASP inhibitors and appear to impact some of the same basic processes as caloric restriction or exercise110,138. Sirtuins facilitate DNA damage repair, partially relying on oxidized NAD+ to do so. Senescent cells can decrease NAD+ through SASP activation of the NAD-degrading enzyme CD38 on the surface of macrophages and, remarkably, senolytics partially restore tissue NAD+ levels139,140. NAD+ or NAD precursors can increase healthspan in experimental animals141. The non-feminizing estrogen, 17α-estradiol, declines with aging in females and males and 17α-estradiol treatment extends healthspan and alleviates age-related metabolic dysfunction and inflammation in mice142. As considered above, senolytics can increase α‐Klotho, which is geroprotective, neuroprotective and linked to healthspan in mice19. Interestingly, α‐Klotho overexpression‎ in mice increases healthspan and lifespan by up to 30% (ref. 143). Hence, consistent with the Unitary Theory, interventions targeting the different fundamental aging mechanisms appear to alleviate aging phenotypes, delay, prevent or treat multiple diseases, and extend healthspan in preclinical models. Testing combinations of these lifestyle, nutritional, natural product and pharmacologic interventions may be informative. However, if the Unitary hypothesis is correct, they may contribute less-than-additive effects because fundamental aging mechanisms are tightly interconnected. A more promising strategy could be to combine geroscience with disease-specific interventions.

노화의 다른 기둥을 대상으로 하는 노화 과학적 개입에 대한 임상 연구가 현재 진행 중이거나 계획 중입니다. 

칼로리 제한 및 간헐적 단식과 같은 식이 요법은 

동물 모델을 대상으로 한 연구에 따르면 

노화와 관련된 기능 장애 및 질병의 발생을 예방할 수 있습니다134,135. 

운동은 

노화 세포 형성을 지연시키고 

생쥐의 염증, 허약 및 만성 질환 발병을 줄일 수 있습니다136,137. 

메트포르민, 

레스베라트롤, 

라팔로그(라파마이신과 관련된 약제)는

 SASP 억제제이며 칼로리 제한이나 운동과 동일한 기본 과정에 영향을 미치는 것으로 보입니다110,138. 

시르투인은 

DNA 손상 복구를 촉진하며, 

부분적으로 산화된 NAD+에 의존합니다. 

노화 세포는 

대식세포 표면에서 

NAD 분해 효소 CD38의 SASP 활성화를 통해 

NAD+를 감소시킬 수 있으며, 

놀랍게도 세놀라아제는 조직 NAD+ 수준을 부분적으로 회복시킵니다139,140. 

NAD+ 또는 NAD 전구체는 

실험 동물의 건강 수명을 늘릴 수 있습니다141. 

비여성화 에스트로겐인 17α-에스트라디올은 

암컷과 수컷의 노화에 따라 감소하며, 

17α-에스트라디올 치료는 생쥐의 건강 수명을 연장하고 

노화와 관련된 대사 기능 장애 및 염증을 완화합니다142. 

위에서 살펴본 바와 같이, 

노화 방지제는 

생쥐의 노화 방지, 

신경 보호 및 건강 수명과 관련이 있는 

α-Klotho를 증가시킬 수 있습니다19. 

흥미롭게도 

생쥐에서 α-Klotho가 과발현되면 

건강수명과 수명이 최대 30%까지 증가합니다(참조 143). 

따라서 단일 이론에 따라 다양한 근본적인 노화 메커니즘을 표적으로 하는 개입은 전임상 모델에서 노화 표현형을 완화하고, 여러 질병을 지연, 예방 또는 치료하며, 건강 수명을 연장하는 것으로 보입니다. 

이러한 

생활습관, 

영양, 

천연물 및 약리학적 개입의 조합을 테스트하는 것은 유익한 정보가 될 수 있습니다. 

그러나 단일 가설이 맞다면, 

근본적인 노화 메커니즘이 서로 긴밀하게 연결되어 있기 때문에 

부가적인 효과에 비해 기여도가 낮을 수 있습니다. 

보다 유망한 전략은 노화 과학과 질병별 중재를 결합하는 것입니다.

Conclusions

The elimination of senescent cells has emerged as a plausible therapeutic strategy for preventing, delaying or alleviating multiple diseases and age-related dysfunction. Promising results of senolytics in preclinical models suggest therapeutic and preventive opportunities for delaying multimorbidity and increasing healthspan. While randomized controlled trials will define the safety and potential benefits of senolytic strategies, scientific and regulatory challenges must be addressed in the near term if senolytics are to be used in the clinic (Box 1).

노화 세포의 제거는 

여러 질병과 노화 관련 기능 장애를 

예방, 지연 또는 완화하기 위한 

그럴듯한 치료 전략으로 부상했습니다. 

전임상 모델에서 

노화 억제제의 유망한 결과는 

다발성 이환을 지연시키고 

건강 수명을 늘릴 수 있는 치료 및 예방 기회를 시사합니다. 

무작위 대조 임상시험을 통해 노인성 질환 치료 전략의 안전성과 잠재적 이점을 확인할 수 있지만, 노인성 질환 치료제를 임상에서 사용하려면 단기간에 과학적 및 규제적 과제를 해결해야 합니다(박스 1).

A key priority should be the identification of reliable, sensitive and specific gerodiagnostics—biomarkers to quantify senescent cell abundance, the SASP and senolysis as well as other pillars of aging. Interventions modulating the SASP (including those that specifically upregulate or downregulate tissue-destructive factors versus growth factors) or topical senolytic agents, especially those that eliminate senescent cells with a proapoptotic SASP, could accelerate wound healing, a possibility that needs to be experimentally tested and correlated with predictive gerodiagnostics.

핵심 우선순위는 

노화 세포의 풍부함, 

SASP, 

노화 분해 및 기타 노화의 기둥을 정량화할 수 있는 

신뢰할 수 있고 민감하며 구체적인 노화 진단 바이오마커를 식별하는 것입니다. 

SASP를 조절하는 개입(성장 인자 대비 조직 파괴 인자를 특별히 상향 조절하거나 하향 조절하는 개입 포함) 또는 

국소적인 노화 세포 분해제, 

특히 세포 사멸을 촉진하는 SASP를 가진 노화 세포를 제거하는 개입은 

상처 치유를 가속화할 수 있으며, 

이는 실험적으로 테스트하고 예측적 노화 진단과 연관시켜야 할 가능성도 있습니다.

The lack of WHO International Classification of Disease (ICD) codes for multimorbidity, sarcopenia, healthspan or the geriatric syndromes represents a barrier to clinical development. Such ICD codes would facilitate regulatory approvals, recording of conditions linked to fundamental aging processes in hospital and insurance records, epidemiological studies, physician and hospital reimbursement and engagement of the pharmaceutical industry. The possible interdependencies among fundamental aging mechanisms need to be investigated to deepen our knowledge about basic aging mechanisms and disease etiologies and to develop treatment strategies to reduce multimorbidity and enhance healthspan.

다발성 질환, 

근감소증, 

건강 수명 또는 

노인 증후군에 대한 WHO 국제질병분류(ICD) 코드가 없다는 것은 

임상 개발의 장벽이 되고 있습니다. 

이러한 ICD 코드는 규제 승인, 병원 및 보험 기록에 근본적인 노화 과정과 관련된 질환의 기록, 역학 연구, 의사 및 병원 환급, 제약 업계의 참여를 촉진할 수 있습니다. 기본적인 노화 메커니즘과 질병 원인에 대한 지식을 심화시키고, 다발성 이환을 줄이고 건강 수명을 늘리기 위한 치료 전략을 개발하기 위해 근본적인 노화 메커니즘 간의 상호 의존성을 조사할 필요가 있습니다.

Finally, a note of caution is important. Even though preclinical data are promising, unless and until carefully monitored, rigorous clinical trials demonstrate safety and effectiveness of senolytics or SASP inhibitors, they should not be endorsed for the prevention or treatment of diseases over-the-counter or in clinical practice. In the meantime, the results of ongoing and planned clinical trials will yield informative data and insights into the role of cellular senescence as a therapeutic target for age-related disorders, potentially enabling translation of small-molecule senolytics into the clinic in the near future.

마지막으로 한 가지 주의할 점이 있습니다. 

전임상 데이터가 유망하다고 하더라도, 

세심한 모니터링과 엄격한 임상시험을 통해 

세놀릭스 또는 SASP 억제제의 안전성과 효과가 입증되지 않는 한, 

일반의약품이나 임상에서 질병의 예방 또는 치료제로 승인해서는 안 됩니다. 

한편, 현재 진행 중이거나 계획 중인 임상시험의 결과는 노화 관련 질환의 치료 표적으로서 세포 노화의 역할에 대한 유익한 데이터와 통찰력을 제공하여 가까운 미래에 저분자 세놀리제를 임상에 도입할 수 있게 할 것입니다.

Box 1 Scientific, logistical and regulatory obstacles

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