Re: Telomere dysfunction in ageing and age-related diseases

[문형철]

Nat Cell Biol

. Author manuscript; available in PMC: 2022 Apr 6.

Published in final edited form as: Nat Cell Biol. 2022 Feb 14;24(2):135–147. doi: 10.1038/s41556-022-00842-x

Telomere dysfunction in ageing and age-related diseases

Francesca Rossiello 1, Diana Jurk 2,3, João F Passos 2,3,✉, Fabrizio d’Adda di Fagagna 1,4,✉

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PMCID: PMC8985209  NIHMSID: NIHMS1792885  PMID: 35165420

The publisher's version of this article is available at Nat Cell Biol

Abstract

Ageing organisms accumulate senescent cells that are thought to contribute to body dysfunction. Telomere shortening and damage are recognized causes of cellular senescence and ageing. Several human conditions associated with normal ageing are precipitated by accelerated telomere dysfunction. Here, we systematize a large body of evidence and propose a coherent perspective to recognize the broad contribution of telomeric dysfunction to human pathologies.

초록

노화하는 생물체는

신체 기능 장애에 기여하는 것으로 추정되는 노화 세포를 축적합니다.

텔로미어 단축과 손상은

세포 노화와 노화의 알려진 원인입니다.

정상적인 노화와 관련된 여러 인간 질환은

가속화된 텔로미어 기능 장애에 의해 촉발됩니다.

본 연구에서는 방대한 증거를 체계화하고,

텔로미어 기능 장애가 인간 질환에 미치는 광범위한 기여를 인식하기 위한 일관된 관점을 제안합니다.

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Telomeres are the genomic portions at the ends of linear chromosomes. Telomeric DNA in vertebrates is made of TTAGGG repeats bound by a set of proteins that modulate their biological functions and protect them from being recognized as DNA damage that triggers a DNA damage response (DDR). As standard DNA polymerases cannot fully replicate linear DNA templates in the absence of telomerase, a DNA-template-independent DNA polymerase, and because of nucleolytic processing, DNA replication results in the generation of chromosomes with progressively shortened telomeres1. As telomeres reach a critical length, they become unable to bind enough telomere-capping proteins and are sensed as exposed DNA ends2, which activates the DDR pathways that, through the induction of the cell cycle inhibitors p21 and p16, arrest proliferation3,4. Such short telomeres, however, retain a sufficient number of telomere-binding proteins to inhibit DNA repair and avoid fusions5, and consequently fuel a persistent DNA damage signal that enforces a permanent DNA damage-induced proliferative arrest. This initiates and maintains cellular senescence, a key contributor to organismal ageing and multiple age-related diseases6,7. Activation of the DDR at telomeres (termed tDDR here-after) results in the formation of telomere-associated DDR foci (TAFs) or telomere-induced DNA damage foci (TIFs), which are markers of cellular senescence in cultured cells and tissues (Box 1). Following telomere dysfunction, some cell types may also undergo cell death by apoptosis8,9 or autophagy10.

텔로미어는

선형 염색체의 끝부분에 위치한 유전체 영역입니다.

척추동물에서 텔로미어 DNA는

TTAGGG 반복 서열로 구성되며,

이 서열은 생물학적 기능을 조절하고

DNA 손상으로 인식되어 DNA 손상 반응(DDR)을 유발하는 것을 방지하는

단백질 복합체에 의해 결합되어 있습니다.

표준 DNA 중합효소는

텔로머레이즈(DNA 템플릿에 의존하지 않는 DNA 중합효소)가 결여된 상태에서

선형 DNA 템플릿을 완전히 복제할 수 없으며,

핵산 분해 과정으로 인해 DNA 복제는 점차적으로 텔로미어가 짧아지는 염색체를 생성합니다1.

텔로미어가 임계 길이에 도달하면

충분한 텔로미어 캡핑 단백질을 결합할 수 없게 되어

노출된 DNA 끝으로 인식됩니다2,

이는

세포 주기 억제제 p21과 p16의 유도 통해 증식을 중단시키는

DDR 경로를 활성화합니다3,4.

그러나 이러한 짧은 텔로미어는

DNA 복구를 억제하고 융합을 방지하기에 충분한 양의 텔로미어 결합 단백질을 유지합니다5.

이로 인해 지속적인 DNA 손상 신호가 발생하여

영구적인 DNA 손상 유발 증식 정지를 강제합니다.

이는 세포 노화(cellular senescence)를 초래하고 유지하며,

이는 유기체 노화와 다양한 노화 관련 질환의 주요 요인입니다6,7.

텔로미어에서 DDR이 활성화되면 (이하 tDDR로 칭함)

텔로미어 관련 DDR 초점 (TAF) 또는 텔로미어에 의한 DNA 손상 초점 (TIF)이 형성되며,

이는 배양된 세포 및 조직에서 세포 노화의 지표로 작용합니다 (박스 1).

텔로미어 기능 장애에 이어,

일부 세포 유형은 세포 사멸8,9 또는

자가포식10을 통해 세포 사멸을 겪을 수도 있습니다.

Box 1 |. Methods to determine telomere length and dysfunction.

A wide range of methods have been developed to measure telomere length (reviewed in ref.200). These include the following techniques: (1) Southern blotting, which measures mean telomere length using the length distribution of the terminal restriction fragments; (2) quantitative PCR (qPCR), which measures the ratio of telomere repeat copy number to single copy gene copy number; (3) single telomere length analysis (STELA), in which telomeres of individual chromosomes are PCR-amplified and their length is then measured by gel electrophoresis; and (4) telomere shortest length assay (TeSLA), which measures the lengths of all the telomeres, including the shortest telomeres, without detecting interstitial telomeric sequences. These methods enable the assessment of telomere lengths with differing degrees of sensitivity in homogenized tissues and cells, but not at the single-cell level. qPCR is the most frequently used method in large-scale epidemiological studies (mostly in blood cells), as it is easier to perform, more cost-effective and easily adaptable to high-throughput processes compared to Southern blotting, STELA or TeSLA. Recently, a non-PCR assay using QuantiGene chemistry on a Luminex platform was developed that facilitates high-throughput measurements of mean telomere length in different tissues40.

상자 1 |. 텔로미어 길이 및 기능 장애 측정 방법.

텔로미어 길이를 측정하기 위해 다양한 방법이 개발되었습니다(참조200). 다음 기술이 포함됩니다:

(1) Southern blotting: 말단 제한 조각의 길이 분포를 통해 평균 텔로미어 길이를 측정합니다;

(2) 정량적 PCR(qPCR): 텔로미어 반복 복사본 수와 단일 복사본 유전자 복사본 수의 비율을 측정합니다;

(3) 단일 텔로미어 길이 분석(STELA): 개별 염색체의 텔로미어를 PCR 증폭한 후 겔 전기영동으로 길이를 측정하는 방법; 및

(4) 텔로미어 최단 길이 검사(TeSLA): 간질 텔로미어 시퀀스를 검출하지 않고 모든 텔로미어(최단 텔로미어 포함)의 길이를 측정하는 방법.

이 방법들은 동질화된 조직 및 세포에서 텔로미어 길이를 서로 다른 민감도로 평가할 수 있지만, 단일 세포 수준에서는 불가능합니다. qPCR은 대규모 역학 연구(주로 혈액 세포에서)에서 가장 널리 사용되는 방법입니다. 이는 Southern blotting, STELA 또는 TeSLA에 비해 수행이 더 쉽고 비용 효율적이며 고효율 프로세스에 쉽게 적응할 수 있기 때문입니다. 최근에는 Luminex 플랫폼을 사용한 QuantiGene 화학 기반의 PCR 비의존적 검사가 개발되어 다양한 조직에서 평균 텔로미어 길이의 고효율 측정이 가능해졌습니다40.

For assessment of telomere length at the single-cell level, other methods have been developed such as fluorescence in situ hybridization (FISH) with telomere peptide nucleic acid (PNA) probes that can be measured by flow cytometry (Flow-FISH) or in tissue sections by fluorescence microscopy (qFISH). Among these methods, Flow-FISH is the most commonly used in epidemiological studies, particularly in peripheral blood. However, in contrast to qFISH, it does not allow the determination of individual telomere lengths per cell. qFISH also has limitations as it does not detect telomeres with a number of telomeric repeats below a threshold sufficient for PNA probe hybridization and detection.

단일 세포 수준에서 텔로미어 길이를 평가하기 위해 다른 방법들이 개발되었습니다. 예를 들어, 텔로미어 펩타이드 핵산(PNA) 프로브를 사용한 형광 현미경 위치 하이브리드화(FISH)는 유동 세포 측정법(Flow-FISH)이나 조직 절편에서 형광 현미경으로 측정할 수 있습니다(qFISH). 이 중 Flow-FISH는 역학 연구, 특히 말초 혈액에서 가장 널리 사용됩니다. 그러나 qFISH와 달리 세포당 개별 텔로미어 길이를 측정할 수 없습니다. qFISH는 또한 PNA 프로브 하이브리드화 및 검출에 충분한 텔로미어 반복 수 미만의 텔로미어를 탐지하지 못한다는 한계가 있습니다.

Although there is a wealth of literature that has investigated telomere length dynamics during ageing and diseases, few studies have explored whether short or damaged telomeres activate the DDR pathways. At present, there are several reliable methods to investigate telomere dysfunction based on the activation and accumulation of DDR proteins at telomeres. tDDR can be eval‎uated in homogenized populations of cells or tissues using methods such as chromatin immunoprecipitation, or at single-cell resolution using immuno-FISH, which allows the visualization of the colocalization between telomeres (detected by a telomere FISH probe) and DDR proteins, such as γH2AX or 53BP1, among others, as detected by immunostaining in the form of TAFs. The key advantage of this method is the possibility of measuring individual events at the single-cell level and the ability to discern whether DDR is activated at short or long telomeres.

The discovery that sites of DNA damage trigger the synthesis of noncoding RNAs (named dilncRNA and DDRNA196 (Box 2)) that carry the sequence of the damaged site provides an opportunity to detect and measure DNA damage, including telomere dysfunction, based on RNA detection or amplification. Measurements of telomeric noncoding RNA can be carried out either in bulk (by qPCR with reverse transcription) or in situ (by FISH or RNAscope)198.

In addition to irreversible cell cycle arrest, cellular senescence is characterized by changes in chromatin, gene expression‎, organelles and cell morphology11. Importantly, senescent cells secrete a complex set of pro-inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). This alters the composition of the extracellular matrix, impairs stem cell functions, promotes cell transdifferentiation and can spread the senescence phenotype to surrounding cells, thereby causing systemic chronic inflammation12. SASP is both promoted by DDR13 and can promote DDR and TAF formation in an autocrine and paracrine fashion14–16.

Although conceptually appealing to explain proliferative exhaustion and cell ageing, telomere shortening is inadequate to explain ageing in non-proliferating, quiescent or terminally differentiated cells. Nevertheless, TAFs and senescence have been reported in ageing post-mitotic cells, including cardiomyocytes, adipocytes, neurons, osteocytes and osteoblasts17. These observations can be explained by an evolutionary perspective by which telomere-binding proteins inhibit DNA repair in cis18,19 to maintain the linear structure of chromosomes and to prevent fusions. As a consequence, DNA damage that occurs within telomeric repeats (tDD) resists repair, which causes persistent tDDR signalling and TAF formation also at long telomeres19–21. Endogenous or exogenous DNA damage is constantly generated, and the fraction that occurs at telomeres, which is less efficiently repaired, thus accumulates and induces a senescence-like phenotype (Fig. 1a).

노화 및 질병 과정에서 텔로미어 길이 동역학을 조사한 문헌은 풍부하지만, 짧은 또는 손상된 텔로미어가 DDR 경로를 활성화하는지 탐구한 연구는 드뭅니다. 현재 텔로미어 기능 장애를 조사하기 위해 텔로미어에서 DDR 단백질의 활성화 및 축적을 기반으로 한 여러 신뢰할 수 있는 방법이 존재합니다. tDDR은 염색질 면역침전법과 같은 방법을 사용하여 세포나 조직의 균질화된 인구에서 평가될 수 있으며, 단일 세포 해상도에서는 면역-FISH를 통해 텔로미어(텔로미어 FISH 프로브로 검출)와 γH2AX 또는 53BP1과 같은 DDR 단백질의 공위치를 시각화할 수 있습니다. 이 단백질들은 면역염색을 통해 TAFs 형태로 검출됩니다. 이 방법의 주요 장점은 단일 세포 수준에서 개별 사건을 측정할 수 있으며, DDR이 짧은 텔로미어나 긴 텔로미어에서 활성화되었는지 구분할 수 있다는 점입니다.

DNA 손상 부위가 손상 부위의 시퀀스를 포함하는 비코딩 RNA(dilncRNA 및 DDRNA196 (Box 2))의 합성을 유발한다는 발견은 RNA 검출 또는 증폭을 기반으로 DNA 손상(텔로미어 기능 장애 포함)을 탐지하고 측정할 수 있는 기회를 제공합니다. 텔로미어 비코딩 RNA의 측정은 대량(역전사 후 qPCR) 또는 in situ(FISH 또는 RNAscope) 방법으로 수행될 수 있습니다198.

세포 주기 정지 외에도 세포 노화는

염색질, 유전자 발현, 세포 소기관 및 세포 형태의 변화로 특징지어집니다11.

중요하게도,

노화 세포는

염증성 사이토카인의 복잡한 세트인 노화 관련 분비 형질(SASP)을 분비합니다.

이는 세포외 기질의 구성 변화를 유발하고 줄기 세포 기능을 손상시키며 세포 전분화를 촉진하며,

주변 세포에 노화 형질을 확산시켜

전신 만성 염증을 유발할 수 있습니다12.

SASP는 DDR에 의해 촉진되며13,

자가분비 및 파라크린 방식으로

DDR과 TAF 형성을 촉진할 수 있습니다14–16.

개념적으로 증식 고갈과 세포 노화를 설명하는 데 매력적이지만,

텔로미어 단축은 증식하지 않는,

휴지 상태 또는 최종 분화된 세포에서의 노화를 설명하기에는 불충분합니다.

그러나 TAF와 노화는

심근세포, 지방세포, 신경세포, 골세포 및 골모세포와 같은 노화 후

분열을 멈춘 세포에서 보고되었습니다17.

이러한 관찰은

텔로미어 결합 단백질이 DNA 수리를 cis에서 억제하여 염색체의 선형 구조를 유지하고 융합을 방지한다는

진화적 관점에서 설명될 수 있습니다18,19.

결과적으로

텔로미어 반복 서열 내(tDD)에서 발생하는 DNA 손상은

수리에 저항하며, 이는 긴 텔로미어에서도 지속적인 tDDR 신호전달과 TAF 형성을 유발합니다19–21.

내인성 또는 외인성 DNA 손상은 지속적으로 발생하며,

텔로미어에서 발생하는 손상의 일부는

수리가 덜 효율적으로 이루어지기 때문에 축적되어 노화 유사 형질을 유도합니다(그림 1a).

Fig. 1 |. Telomere shortening and damage and their consequences.

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a, Genomic DNA damage (DD) triggers a transient DNA damage response (DDR) that may not be sufficient for senescence establishment. Alternatively, an irreparable, therefore persistent, DNA damage at telomeres causes a protracted DDR and cellular senescence that are associated with SASP-mediated inflammation and consequent fibrosis. These events in a stem-cell context impair stem-cell properties and alter differentiation. Overall this contributes to organismal ageing17. b, In proliferating tissues, telomeres are shortened with cell cycle divisions and, when critically short, they trigger a DDR. In non-proliferating, post-mitotic tissues, telomere dysfunction can be driven by irreparable DNA damage within telomeres. In both cases, the persistent DDR activation sustains a senescent phenotype that is characterized by arrested proliferation and SASP activation.

Therefore, persistent tDDR activation is the shared causative event of both replicative cellular senescence caused by critically short telomeres and the senescence-like state caused by damaged telomeres in non-replicating cells (Fig. 1b). Although these events may be mechanistically distinct in origin, DNA damage at long telomeres may cause, within the time frame of organismal ageing, degradation or loss of the terminal portions of telomeres, therefore leading to telomere shortening.

In the broader context of organismal ageing, the notion that DNA is the only irreplaceable component of the cell makes a strong argument in favour of an apical role of DNA integrity in ageing. The irreparability of telomeres makes it more so.

In addition to being hard to repair, telomeric DNA is hyper-sensitive to oxidative DNA damage, a phenomenon recently named TelOxidation22. Oxidative stress reportedly both induces tDD without telomere shortening and accelerates telomere shortening23–26 by inhibiting telomerase27 and disrupting the recognition by telomere-binding proteins, which contributes to telomere uncapping22,28.

a, 유전체 DNA 손상(DD)은 일시적인 DNA 손상 반응(DDR)을 유발하지만, 이는 노화 확립에 충분하지 않을 수 있습니다. 대안적으로, 텔로미어에서 수리 불가능하고 따라서 지속되는 DNA 손상은 연장된 DDR과 세포 노화를 유발하며, 이는 SASP 매개 염증과 후속 섬유화와 연관됩니다. 이러한 사건은 줄기세포 맥락에서 줄기세포 특성을 손상시키고 분화를 변화시킵니다. 전체적으로 이는 유기체 노화에 기여합니다17.

b, 증식 조직에서 텔로미어는 세포 주기 분열과 함께 단축되며, 극도로 짧아지면 DDR을 유발합니다. 증식하지 않는 분열 후 조직에서는 텔로미어 내의 복구 불가능한 DNA 손상이 텔로미어 기능 장애를 유발할 수 있습니다. 두 경우 모두 지속적 DDR 활성화는 증식 중단과 SASP 활성화로 특징지어지는 노화 표현형을 유지합니다.

따라서, 지속적 tDDR 활성화는 극도로 짧은 텔로미어로 인한 복제성 세포 노화와 비복제 세포에서 손상된 텔로미어로 인한 노화 유사 상태의 공통된 원인 사건입니다(그림 1b). 이러한 사건들은 기전적으로 서로 다른 기원을 가질 수 있지만, 장수 텔로미어에서의 DNA 손상은 유기체 노화 과정에서 텔로미어의 말단 부위 퇴화 또는 손실을 초래하여 텔로미어 단축으로 이어질 수 있습니다.

생물체 노화의 더 넓은 맥락에서, DNA가 세포의 유일한 대체 불가능한 구성 요소라는 사실은 DNA 무결성의 노화에서의 정점적 역할을 강력히 뒷받침합니다. 텔로미어의 수리 불가능성은 이를 더욱 강화합니다.

텔로미어 DNA는 수리가 어려운 데 더해 산화성 DNA 손상에 극도로 민감하며, 이 현상은 최근 '텔옥시데이션'으로 명명되었습니다22. 산화 스트레스는 텔로미어 단축 없이 tDD를 유도하며, 텔로머레이즈 억제27과 텔로미어 결합 단백질의 인식 장애를 통해 텔로미어 단축을 가속화합니다23–26. 이는 텔로미어 캡 제거에 기여합니다22,28.

tDDR activation and TAF accumulation are often causally connected to other ageing-associated processes. These include mitochondrial dysfunction, altered nutrient sensing, impaired autophagy, loss of proteostasis and epigenetic dysregulation, which suggests that there is a unifying ‘telomere-centric’ mechanistic rationale for many ageing hallmarks, as also proposed in ref.29.

tDDR 활성화 및 TAF 축적은 종종 다른 노화 관련 과정과 인과적으로 관련이 있습니다. 여기에는 미토콘드리아 기능 장애, 영양소 감지 변화, 자가포식 장애, 단백질 항상성 상실 및 후성 유전적 조절 장애가 포함되며, 이는 참고 문헌 29에서 제안한 바와 같이 많은 노화의 특징에 대해 '텔로미어 중심'의 통합적인 기계적 근거가 있음을 시사합니다.

Telomere dysfunction during ageing.

As replicative cellular senescence is caused by telomere shortening below a critical length1, the effect of telomere shortening on organismal ageing in animal models, primarily mouse and fish species, has mostly been studied through genetic deletion of telomerase component genes, either the telomerase RNA component (Terc) or the telomerase reverse transcriptase protein (Tert), and successive inbreedings. In these models, telomere shortening progressively causes tDDR activation and cellular senescence, which recapitulates features of ageing and age-related diseases30,31. Across species, however, short telomeres do not necessarily predict short lifespan—that is, humans have shorter telomeres but longer lifespans than rodents. Instead, telomere shortening rates and the increase in short telomeres has been proposed to predict lifespan32. Consistently, one or a few critically short telomeres are sufficient to trigger a DDR and impose cellular senescence in vivo, regardless of a majority of otherwise long telomeres33. Thus, individual DDR signalling events at telomeres are key determinants of cell fate and organismal ageing. Indeed, the levels of DDR markers and TAFs increase during ageing in different mammalian tissues. Mice, despite having long telomeres and ubiquitous telomerase expression‎, show an age-dependent increase in dysfunctional telomeres in both proliferating and non-proliferating tissues20,34–37. Damaged telomeres also increase in the brain, liver and skin of aged baboons19,38. In humans, TAFs increase with age in the absence of telomere shortening in skin melanocytes15 and CD8+ T cells, together with other senescence markers39. Although most human data on telomeres are based on studies of leukocytes, a recent study of telomere length in tissues from 952 individuals concluded that 21 out of the 24 tissues studied show age-dependent telomere shortening40.

Several pieces of evidence support a role for tDDR as a driver of ageing and age-associated diseases. First, interventions known to increase health span such as dietary restriction41, exercise42, rapamycin43,44 and 17β-oestradiol45 can reduce the frequency of cells with TAFs. Clearance of senescent cells with senolytic strategies reduces TAF numbers in vivo36,37,41,46. Conversely, TAFs accumulate after chronic inflammation47, obesity37,41, mitochondrial dysfunction36 and impaired autophagy48, which are all known to accelerate ageing.

The most preval‎ent hypothesis is that it is not telomere dysfunction per se that leads to ageing and age-associated diseases but telomere dysfunction-activated tDDR that causes cellular senescence, which, also by SASP, facilitates the age-related loss of tissue functions11. Although senescence may occur independently of telomere dysfunction17 (for example, during development), the differential contribution of telomere-dependent and -independent cellular senescence to ageing and age-related disorders remains to be determined.

Here, we review the role of telomere dysfunction in the context of human ageing and age-related diseases, often termed telomeropathies, telomere biology disorders or telomere syndromes (Fig. 2 and Table 1). Although we describe diseases individually, grouped by the organs affected, individual patients with telomeropathies often show more than one clinical manifestation, which supports the notion of a “spectrum disorder”49 caused by telomere dysfunction.

노화 동안의 텔로미어 기능 장애.

복제성 세포 노화는 텔로미어가 임계 길이를 밑돌면서 발생합니다1. 따라서 동물 모델(주로 쥐와 어류 종)에서 텔로미어 단축이 유기체 노화에 미치는 영향은 주로 텔로머레이스 구성 유전자(텔로머레이스 RNA 구성 요소(Terc) 또는 텔로머레이스 역전사 효소 단백질(Tert))의 유전적 삭제와 후속 근친 교배를 통해 연구되었습니다. 이러한 모델에서 텔로미어 단축은 점차적으로 tDDR 활성화와 세포 노화를 유발하며, 이는 노화와 노화 관련 질환의 특징을 재현합니다30,31. 그러나 종 간에는 짧은 텔로미어가 반드시 짧은 수명을 예측하지는 않습니다—즉, 인간은 설치류보다 텔로미어가 짧지만 수명이 더 깁니다. 대신 텔로미어 단축 속도와 짧은 텔로미어의 증가가 수명을 예측한다는 제안이 제기되었습니다32. 일관되게, 하나 또는 몇 개의 극히 짧은 텔로미어만으로도 DDR을 유발하고 세포 노화를 초래할 수 있으며, 이는 대부분의 텔로미어가 길더라도 마찬가지입니다33. 따라서 텔로미어에서의 개별 DDR 신호 전달 사건은 세포 운명과 유기체 노화의 핵심 결정 요인입니다. 실제로, 다양한 포유류 조직에서 노화 과정에서 DDR 표지자와 TAF의 수준이 증가합니다. 마우스는 긴 텔로미어와 보편적인 텔로머레이스 발현을 가지고 있음에도 불구하고, 증식 및 비증식 조직에서 연령에 따른 기능 장애 텔로미어의 증가를 보여줍니다20,34–37. 손상된 텔로미어는 노화된 바보원의 뇌, 간, 피부에서도 증가합니다19,38. 인간에서는 텔로미어 단축이 없는 피부 멜라노사이트15와 CD8+ T 세포에서 TAF가 증가하며, 다른 노화 표지자도 함께 증가합니다39. 대부분의 인간 텔로미어 데이터는 백혈구 연구에 기반하지만, 952명의 조직에서 텔로미어 길이를 측정한 최근 연구에서는 조사된 24개 조직 중 21개에서 연령에 따른 텔로미어 단축이 관찰되었습니다40.

여러 증거가 tDDR이 노화와 노화 관련 질환의 촉진제 역할을 한다는 것을 지지합니다. 첫째, 건강 수명을 연장하는 것으로 알려진 개입 방법인 식이 제한41, 운동42, 라파마이신43,44 및 17β-에스트라디올45은 TAF를 가진 세포의 빈도를 감소시킵니다. 노화 세포를 노화 방지 전략으로 제거하면 생체 내에서 TAF 수가 감소합니다36,37,41,46. 반대로, TAF는 만성 염증47, 비만37,41, 미토콘드리아 기능 장애36 및 자가포식 장애48 후에 축적되며, 이러한 모든 요인은 노화를 촉진하는 것으로 알려져 있습니다.

가장 널리 받아들여지는 가설은 텔로미어 기능 장애 자체보다는 텔로미어 기능 장애에 의해 활성화된 tDDR이 세포 노화를 유발하며, 이는 SASP를 통해 조직 기능의 노화 관련 손실을 촉진한다는 것입니다11. 노화는 텔로미어 기능 장애와 독립적으로 발생할 수 있습니다(예: 발달 과정에서)17, 그러나 텔로미어 의존적 및 비의존적 세포 노화가 노화와 연령 관련 질환에 미치는 상대적 기여도는 아직 명확히 규명되지 않았습니다.

여기서는 인간 노화와 노화 관련 질환(흔히 텔로미어 병증, 텔로미어 생물학 장애 또는 텔로미어 증후군이라고도 함)의 맥락에서 텔로미어 기능 장애의 역할을 검토합니다(그림 2 및 표 1). 우리는 질환을 영향을 받는 장기에 따라 개별적으로 설명하지만, 텔로미어 병증을 가진 환자들은 종종 하나의 임상적 증상 이상을 나타내며, 이는 텔로미어 기능 장애에 의해 유발되는 “스펙트럼 장애”49라는 개념을 지지합니다.

Fig. 2 |. Evidence for a role of cellular senescence and telomere dysfunction in age-related diseases.

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Schematic representation of the age-related diseases described in this Review grouped by organs or systems. AA, aplastic anaemia; AD, Alzheimer’s disease; ALD, alcholic liver disease; AMD, age-related macular degeneration; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; IPF, idiopathic pulmonary fibrosis; IRI, ischaemia–reperfusion injury; MDS, myelodysplastic syndrome; NAFLD, non-alcoholic fatty liver disease; PBC, primary biliary cirrhosis; PD, Parkinson’s disease; T2D, type 2 diabetes.

Table 1 |.

List of diseases and supporting evidence

DiseaseTelomere dysfunctionCellular senescenceAnimal modelsRefs.Correlative linkCausal linkCorrelative linkCausal link

Pulmonary diseases	Idiopathic pulmonary fibrosis	In humans: telomere shortening, mutation in telomere-associated genes	In mice: telomerase re-expression‎ in telomerase-deficient model and overexpression‎ in wild-type mice	In humans: senescence markers	In mice: genetic clearance of senescent cells, senolytic drugs	Late-generation telomerase-deficient (Terc−/− or Tert−/− mice treated with low-dose bleomycin, mice with inducible Trf1 or Trf2 knockout in alveolar type II cells	51–64
	Chronic obstructive pulmonary disease	In humans and mice: increased TAFs reduced TPP1 levels, telomere shortening	–	In human cells: senescence markers induced by cigarette smoke	–	Wild-type mice exposed to cigarette smoke, late-generation telomerase-deficient mice	34,66–68
	Non-cystic fibrosis bronchiectasis	In humans: telomere shortening, TAFs	–	In humans: senescence markers	–	–	69
	COVID-19	In humans: telomere shortening	–	–	–	–	71,72
Acquired bone marrow failure syndromes	Aplastic anaemia	In humans: telomere shortening, mutations in telomere-associated genes	In mice: telomere dysfunction-induced disease and reversal by increased telomerase activity	–	–	Mice with Trf1 knockout in the haematopoietic system, late-generation telomerase-deficient (Tert−/−) mice	74–86
	Myelodysplastic syndrome	In humans: telomere shortening, mutations in telomere-associated genes	In mice: telomerase re-expression‎ in telomerase-deficient model	In mice: DNA damage	–	Late-generation telomerase-deficient mice	87,89–91
Metabolic diseases	Metabolic syndrome	In mice: telomere shortening, TAFs	In mice: telomerase-deficient model	–	–	Tissue-specific telomerase-deficient (Tert−/−) mice	37,92,93
	Liver cirrhosis	In humans: telomere shortening, mutations in telomerase genes	In mice: telomerase re-expression‎ in telomerase-deficient model	In humans: SA-β-galactosidase	–	Late-generation telomerase-deficient mice	94–97
	Non-alcoholic fatty liver disease	In humans: TAFs	–	In mice: p21	In mice: senolysis	Tissue-specific DNA repair deficient mice	41
	Primary biliary cirrhosis	In humans: telomere shortening	–	In humans: DDR, senescence markers	In mice: senolytic drugs	Mdr2-knockout mice	98,99
	Alcoholic liver disease	In humans: TAFs	–	–	–	–	100,101
	Type 2 diabetes	In humans: telomere shortening	–	–	In mice: senolytic drugs and genetic clearance of senescent cells	Late-generation telomerase-deficient mice	102,103
Cardiovascular diseases	Myocardial hypertrophy and fibrosis	In mice: length-independent TAFs	–	In mice: p16, p21, SASP	In mice: senolytic drugs and genetic clearance of senescent cells	–	36
	Cardiac ischaemia-reperfusion injury	In mice: TAFs	–	–	In mice: senolytic drugs	–	106
	Hypertrophic and dilated cardiomyopathy	In humans: telomere shortening	In mice: telomerase-deficient model and telomerase re-expression‎ in telomerase-deficient model	–	–	Late-generation telomerase-deficient mice	107–112
	Atherosclerosis	In humans: telomere shortening	In mice: telomere dysfunction model	In humans: senescence markers	In mice: senolytic drugs and genetic clearance of senescent cells	TRF2T188A/Apoe−/− mice	46,114–118
Skeletal disorders	Osteoarthritis	In humans: telomere shortening	–	In humans: DDR, p16, reactive oxygen species accumulation	In mice: senolytic drugs and genetic clearance of senescent cells	Injury-induced osteoarthritis mice	119–127
	Osteoporosis	In humans: telomere shortening	In mice: telomerase-deficient model	–	In mice: senolytic drugs and genetic clearance of senescent cells	Late-generation telomerase-deficient (Terc−/−) mice	129–133
Kidney diseases	Chronic kidney disease	In humans and cats: telomere shortening	In mice: telomerase-deficient model	In humans: DDR, SASP In cats: senescence markers	In mice: genetic clearance of senescent cells	Late-generation telomerase-deficient mice	134–148
	Kidney fibrosis	–	In mice: telomerase-deficient model and telomere dysfunction-dependent disease	–	–	Late-generation telomerase-deficient (Tert−/−) or Trf1-knockout mice	149
Neurodegenerative diseases	Alzheimer’s disease	In humans: telomere shortening. In mice: a potential correlative link to telomere shortening	In mice: telomerase-deficient model and telomerase re-expression‎ in telomerase-deficient model	In humans: DDR, p16, SA-β-galactosidase	In mice: senolytic drugs, genetic clearance of senescent cells	Late-generation telomerase-deficient mice	153–167
	Parkinson’s disease	–	In mice: telomerase-deficient model, telomerase activators	In humans: senescence markers	In mice: genetic clearance of senescent cells	Late-generation telomerase-deficient mice	164,168–171
Eye diseases	Macular degeneration	–	In humans: telomerase activator	In humans and mice: p16, p21, SASP, SA-β-galactosidase	–	–	173–176
Reproductive system diseases	Reduced fertility	In humans: telomere shortening	In mice, zebrafish and killifish: telomerase-deficient model	–	–	Late-generation telomerase-deficient mice, telomerase-deficient zebrafish	177–187

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For each pathology described in the text, the evidence for causality or correlation with telomere dysfunction, cellular senescence and animal model(s) used are listed.

Pulmonary diseases.

Several lung diseases have been associated with ageing50 and causally linked to telomere dysfunction and senescent cell accumulation.

Idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF), which affects approximately 3 million people worldwide, is a lung degenerative disease characterized by interstitial remodelling. Fibrosis in human ageing lungs has been associated with telomere shortening, DDR and cellular senescence51. Patients with IPF accumulate TAFs and senescence markers in lungs that increase with disease severity and activate SASP52. Moreover, circulating leukocytes and alveolar epithelial cells show shorter telomeres than age-matched individuals53. Short telomeres are an established risk factor for IPF, and 37% of familial cases and 25% of sporadic cases show telomere lengths below the tenth percentile for their age, as assessed in circulating leukocytes and alveolar epithelial cells54. In independent cohorts, a shorter telomere length was demonstrated to be a robust independent predictor of disease progression, response to therapy and death55, and to be associated with a shorter time to allograft dysfunction following lung transplant56. Causality of telomere dysfunction in familial and sporadic IPF is indicated by the detection of germline mutations in genes involved in telomere maintenance57,58.

Mouse studies indicate that telomere dysfunction can recapitulate IPF features. Mice with short telomeres induced by knockout of telomerase components show TAFs, inflammation and fibrosis in lungs59, which is aggravated by cigarette smoke60 or a low dose of bleomycin, a DNA-damaging agent61. Telomere dysfunction, specifically induced in alveolar epithelial type II cells through the deletion of the telomere proteins TRF1 or TRF2, led to impaired regeneration, inflammation and fibrosis61,62. Consistently, expression‎ of telomerase using adeno-associated vectors (AAVs) in alveolar epithelial type II cells led to TAF reduction, decreased inflammation and improved lung function in telomerase-mutant and wild-type aged mice63,64. Additionally, genetic or pharmacological clearance of senescent cells improved lung function and health in a mouse model of bleomycin-induced IPF52.

Chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) affects around 300 million people globally and is associated with high morbidity and mortality in elderly patients65. COPD exhibits accelerated lung ageing characterized by inflammation of parenchyma and airways, chronic remodelling of the peripheral bronchi and inter-alveolar septa disruption towards emphysema. Compared with unaffected individuals, small airway epithelial cells from patients with COPD show higher levels of TAFs and senescence markers34. Cigarette smoke (a major risk factor for COPD) induced TAFs, cellular senescence and SASP in cultured primary human airway epithelial cells and fibroblasts34 and reduced telomere protection protein 1 (TPP1) levels in mouse and human lungs, which caused tDDR activation66. Short telomeres were also observed in lungs and circulating leukocytes of patients with COPD66,67. Telomerase mutations are a risk factor for emphysema among patients with COPD68.

Other lung diseases.

Non-cystic fibrosis bronchiectasis is a common inflammatory lung disease characterized by irreversible dilation of the bronchi. Lung tissues from these patients show shorter telomeres and increased levels of TAFs and senescence markers69.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been predicted to cause long-term lung fibrosis70. Disease severity has been correlated with patient age and leukocyte telomere length71, which is consistent with a recent finding that tDDR activation induced by telomere shortening increases the expression‎ of ACE2, the SARS-CoV-2 receptor on human lung cells72.

Acquired bone marrow failure syndromes.

Nucleated blood cells show the shortest telomeres among human tissues40. Thus, it is not surprising that impaired telomere maintenance most acutely impairs haematopoiesis.

Aplastic anaemia.

Aplastic anaemia is a rare disease with a variable age of diagnosis and is characterized by pancytopaenia in the peripheral blood and markedly hypocellular bone marrow73. Around 9% of patients with acquired aplastic anaemia carry mutations in the telomerase components TERC, TERT and DKC1, which are also mutated in inherited aplastic anaemia, as in dyskeratosis congenita74,75. Additional rarer mutations in other telomere homeostasis genes have been identified76–78. About one-third of patients with aplastic anaemia show short telomeres in peripheral blood, which suggests that there is a causative link between aplastic anaemia pathology and telomere dysfunction75,76,79. Patients with shorter telomeres at diagnosis show a more severe disease, a poorer response to treatments, an increased risk of relapse and development of myelodysplastic syndrome (MDS; see below) and a lower survival rate75,80,81. Leukocyte telomere length in the donor, but not in the recipient, positively correlates with survival following allogenic haematopoietic cell transplantation82. The use of the androgen receptor agonist danazol in patients with aplastic anaemia with critically short telomeres improved their condition by increasing telomerase expression‎ and lengthening telomeres. This provides support for a causative role of telomere length in this disease83.

At least two mouse models have demonstrated a causative role of telomere dysfunction in bone marrow failure. First, partial depletion of TRF1 in hematopoietic stem and progenitor cells caused TAF formation, cell depletion and a compensatory proliferation, which resulted in rapid telomere attrition and cellular senescence84. Similarly, transplantation of bone marrow from late-generation Tert-knockout mice in irradiated wild-type recipients resulted in aplastic anaemia85. In both models, danazol or AAV-mediated Tert expression‎ improved haematopoiesis85,86.

MDS.

MDS is a heterogeneous group of clonal haematopoietic disorders characterized by ineffective haematopoiesis and DNA damage accumulation in haematopoietic stem and progenitor cells87. MDS affects up to 13.2 per 100,000 people88, often in advanced age. MDS can also be secondary to chemotherapy or radiation or be associated with inherited abnormalities in DNA repair and telomere maintenance genes89. Bone marrow cells in patients with MDS have shorter telomeres than those in healthy donors90. Moreover, late-generation telomerase-deficient mice recapitulate myelodysplastic features that can be reversed by telomerase reactivation91.

Metabolic diseases.

Metabolic diseases occur when the organism is incapable of efficiently converting food into energy. Here, we summarize the evidence that suggests that telomere dysfunction is a common causal factor in several of these diseases.

Metabolic syndrome.

Estimated to affect one in three people in the United States, metabolic syndrome is a set of related conditions including chronic inflammation, obesity, dyslipidaemia, high blood pressure and insulin resistance co-occurring in an individual, which together increase the risk of serious cardiovascular disease. Similar to the other conditions contributing to it, obesity is associated with increased TAFs in various organs and tissues37,41,92. Short telomeres in adipose tissues are associated with metabolic disease progression, and causality was demonstrated by telomerase inactivation in mouse adipocyte precursors that led to hypertrophy and inflammation93.

Liver diseases.

Telomere shortening has been implicated in hepatocyte senescence94 and in disease progression in patients with liver cirrhosis95. Patients with cirrhosis have a higher incidence of telomerase mutations and bear shorter telomeres than unaffected individuals96. Late-generation telomerase-deficient mice exposed to chronic liver injury show accelerated cirrhosis development97.

Non-alcoholic fatty liver disease (NAFLD) is characterized by an excess of hepatic fat accumulation (steatosis) and, in later stages, inflammation (non-alcoholic steatohepatitis) and fibrosis. TAF and p21 levels in hepatocytes positively correlate with NAFLD severity41, and the clearance of senescent cells in aged and obese mice reduced the fraction of TAF-positive hepatocytes and alleviated liver steatosis41. Primary biliary cirrhosis, an autoimmune disease with chronic, progressive cholestasis and liver failure, is associated with short telomeres, DDR activation and senescence marker accumulation in biliary epithelial cells98. Treatment of a mouse model of biliary liver fibrosis with a senolytic drug reduced fibrosis99. Alcoholic liver disease and chronic viral hepatitis have also been associated with telomere dysfunction in human liver biopsies100,101.

Type 2 diabetes.

Type 2 diabetes (T2D) is an age-associated disease characterized by a decrease in pancreatic β-cell mass and function and insulin resistance in multiple tissues that results in hyperglycaemia. Several cross-sectional human studies of white blood cells have shown an association between T2D and short telomeres102. Mice with short telomeres display impaired insulin secretion and glucose intolerance associated with an accumulation of senescence markers, which suggests a causal role for telomere shortening in this pathology. Senescent cell clearance improved glucose homeostasis and insulin sensitivity in obese and aged mice103.

Cardiovascular diseases.

Cardiovascular diseases are the leading causes of morbidity and mortality in western countries, and ageing is a major risk factor for their development104. Both telomere shortening and telomere damage have been reported as hallmarks and potential drivers of heart diseases and as indicators of therapeutic outcomes105.

Cardiac diseases.

The heart exhibits cardiomyocyte hypertrophy and fibrosis during ageing that leads to increased ventricular stiffness and impaired cardiac function. During physiological ageing in humans and mice, TAFs occur independently from telomere length in post-mitotic cardiomyocytes. This is associated with the induction of p16 and p21 and a cardiac-specific form of SASP that contributes to cardiac hypertrophy and fibrosis36. The clearance of senescent cells in aged mice improves heart functions and reduces the fraction of TAF-positive cardiomyocytes without a significant effect on mean telomere length36. This observation confirm‎s a role for cellular senescence in heart disease and hints at the negligible contribution of telomere length to cardiomyocyte senescence36. Length-independent telomere damage may result from oxidative damage, as mouse models of increased oxidative stress and mitochondrial dysfunction show early onset of age-dependent telomere dysfunction36. Consistently, cardiac ischaemia–reperfusion injury (IRI), which is associated with massive induction of oxidative stress, promotes TAF formation and senescence, and treatment with a senolytic agent improved cardiac function106.

Patients with genetic forms of hypertrophic or dilated cardiomyopathy, conditions that affect 1 in 500–2,500 people worldwide, have cardiomyocytes with shorter telomeres than age-matched individuals107,108. Short telomeres were also observed in a large independent cohort, with the severity of hypertrophic cardiomyopathy correlating with the telomere length of leukocyte telomeres109. A causal role of short and dysfunctional telomeres in cardiac diseases has been established in mice110. Late-generation telomerase-deficient mice show severe left ventricular loss of function, increased cardiomyocyte hypertrophy and decreased number of cardiomyocytes111. AAV-mediated Tert expression‎ in adult mice improved their survival following myocardial infarction112.

Atherosclerosis.

Atherosclerosis is a vascular disease that is characterized by the formation of artery plaques containing vascular smooth muscle cells (VSMCs) that potentially leads to thrombosis and myocardial infarction, and is considered a leading cause of mortality worldwide113. In a limited cohort, patients with atherosclerosis bear shorter telomeres in circulating leukocytes than healthy age-matched individuals114. VSMCs in human atherosclerotic plaques show cellular senescence markers and telomeres that are markedly shorter than those in unaffected vessels from the same individual115. Telomere dysfunction induced by VSMC-specific expression‎ of mutant TRF2 is sufficient to increase atherosclerosis116,117. Indeed, clearance of senescent cells reduced TAF-positive cells in the medial layer of the aorta from aged and hypercholesterolaemic mice46 and alleviated plaque formation and disease progression46,118.

Skeletal disorders.

Changes in bone and joint tissues that lead to osteoporosis and osteoarthritis are associated with an accumulation of senescent cells.

Osteoarthritis.

Osteoarthritis is characterized by the degeneration of joint cartilage and subchondral bone, and affects more than 30 million adults in the United States (https://oaaction.unc.edu/oa-module/oa-preval‎ence-and-burden/). Chondrocytes, the cells that constitute the articular cartilage, show several senescence markers, including DDR activation, in osteoarthritis119,120. A causal role of senescence in this pathogenesis was established by evidence showing that removal of senescent cells reduced the development of post-traumatic and naturally occurring osteoarthritis in mouse models121. Moreover, treatment with a senolytic therapy mitigated age-dependent disc degeneration122. A link between osteoarthritis and telomere dysfunction is supported by the observations that patients with osteoarthritis have leukocytes with shorter telomeres than age-matched individuals123,124, and telomere length inversely correlates with chronic severe pain125. Moreover, cultured chondrocytes isolated from areas close to the osteoarthritis lesions from the hips of patients have shorter mean telomere length and increased levels of senescence markers than those from distal sites in the same joint126. Interestingly, the presence of ultrashort telomeres has been proposed to be a better marker than average telomere length for the extent of osteoarthritis damage127.

Osteoporosis.

Osteoporosis is a chronic skeletal disorder that affects more than 200 million people worldwide. It is characterized by low bone mineral density and microarchitectural deterioration of bone tissues that can lead to an increased fracture risk128. A total of 33% of women and 20% of men over the age of 50 years are estimated to experience osteoporosis-related fractures. Increasing evidence points towards a role for telomere dysfunction and senescence in osteoporosis129. Senescent osteocytes that express p16 at high levels have been associated with age-related bone loss in mice, and their clearance increased bone strength130. Osteoporosis correlates with short telomeres in the leukocytes of patients, and long telomeres in a female cohort were associated with high bone mineral density and reduced risk of osteoporosis131. Supporting a causal role of telomere dysfunction in osteoporosis, late-generation telomerase-deficient mice recapitulate several features of osteoporosis, such as decreased bone volume, diminished osteoblast number and function, and increased porosity, with TAFs being associated with impaired osteoblast differentiation132,133.

Kidney diseases.

During physiological ageing, kidneys experience detrimental structural and functional changes. Several renal pathologies such as acute kidney injury, glomerulonephritis, diabetic nephropathy, polycystic kidney disease and chronic kidney disease (CKD) have been associated with cellular senescence and telomere dysfunction134.

CKD, which is estimated to affect 15% of the adult population in the United States (https://www.kidney.org/news/newsroom/fsindex), is an independent risk factor for cardiovascular events in older people, often leading to end-stage renal disease. Dialysis and kidney transplant remain the only two major treatments. CKD shows several features of accelerated ageing, including decreased kidney weight, atrophy, sclerosis, fibrosis and a CKD-associated secretory phenotype, which is similar to SASP135. In CKD, senescence markers were observed in tubular epithelial cells, podocytes, interstitial and mesangial cells136, and their accumulation was associated with disease progression135.

DNA damage accumulates in many forms of kidney injury. Kidneys in patients with CKD exhibited an increased number of tubules positive for the DDR marker γH2AX, which was inversely correlated with the estimated glomerular filtration rate, and a greater number of phosphorylated ATR-positive cells137. Increased levels of γH2AX and phosphorylated ATM in glomeruli are associated with clinicopathological parameters in patients with IgA nephropathy, a condition that often leads to CKD138. Thus, DDR activation and senescence alone or in combination with insults such as infections, lipopolysaccharides, uraemic toxins and dialysis treatments, can contribute to CKD139,140.

In patients with uraemia, a sign of kidney damage, lymphocyte telomere length was significantly shorter than in unaffected individuals141. A study of a large cohort of patients with CKD revealed that telomere length measured in peripheral blood was a strong independent predictor of all-cause mortality142. Moreover, in a large population study, telomere shortening was associated with an increased risk for CKD progression in individuals who actively smoke and in patients with diabetes mellitus143. Telomere length predicts long-term kidney allograft function, and telomere shortening is linked to complications of kidney transplantation144.

Animal studies suggest that telomere dysfunction is causally implicated in kidney ageing, acute kidney injury and decreased recovery after insult. Mice with dysfunctional telomeres show an age-dependent decline in kidney function and morphology145 as well as reductions in renal function and regeneration after IRI146. In aged mice, clearance of senescent cells reduced glomerulosclerosis and retained blood urea nitrogen levels, which indicates that senescence contributes to these pathological alterations147. Cats with CKD also show shortened telomeres and increased numbers of senescent cells in the kidney148.

Recently, strong evidence has linked telomere shortening and dysfunction with kidney fibrosis. In two independent mouse models, short and dysfunctional telomeres were shown to sensitize kidneys to folic acid-induced toxicity that resulted in fibrosis, thereby demonstrating a key contribution of telomere dysfunction in this pathology149.

Neurodegenerative diseases.

Brain ageing is characterized by a progressive decline in memory and cognition and is recognized as the greatest risk factor for neurodegenerative diseases. Senescent cells accumulate with age in the murine brain and is exacerbated in late-generation telomerase-deficient mice150, which suggests a causal role for telomere dysfunction in this process. Indeed, TAFs increase with age in hippocampal neurons in baboons19 and mice151. Age-dependent TAF increases in the brain also correlate with chronic inflammation151 and obesity37, both of which are associated with age-dependent cognitive decline. Single-cell RNA sequencing of the hippocampus of aged mice revealed an increased p16 level with age, which was stronger in microglia and oligodendrocyte progenitor cells152. Clearance of senescent cells in aged mice significantly improved cognitive function152, which indicates that senescence has an important role in age-associated cognitive impairment.

Alzheimer’s disease.

Alzheimer’s disease is the most common cause of dementia and affects around 10% of people over the age of 65 years (https://www.alz.org/alzheimers-dementia/facts-figures). Cellular senescence markers have been reported in neurons and astrocytes from patients with Alzheimer’s disease and in cultured human astrocytes exposed to β-amyloid153. DNA damage and DDR markers have been observed in models of Alzheimer’s disease154,155 and in neurons in postmortem brains from patients with the disease156. Neuronal cell death, a characteristic of Alzheimer’s disease, is thought to be a consequence of microglia senescence, and telomeres in microglia were reported to be shorter in patients with the disease than in healthy individuals157.

Genetic clearance of senescent cells or senolytic treatment in tauopathy mouse models mitigated cognitive decline and neurode-generation158,159, which suggests that cellular senescence has a causative effect in this pathology. Similarly, treatment of an Alzheimer’s disease mouse model with a senolytic agent improved memory and learning ability160.

Although blood cells from patients with Alzheimer’s disease were found to have shorter telomeres, the role of telomere length is controversial161. In a mouse model of Alzheimer’s disease, shorter telomeres were found in blood cells but not in the hippocampus compared to wild-type mice162. Across patients with amyloid pathology, leukocyte telomere length positively correlated with better cognition and memory, whereas cognitive decline over 2 years was steeper in patients with the lowest quartile of telomere length, who also have a greater chance of developing dementia163. In support of a role of short telomeres in neurodegenerative diseases, late-generation telomerase-deficient mice recapitulate Alzheimer’s disease phenotypes164. Notably, AAV-mediated Tert expression‎ ameliorated memory impairment164. Telomerase appears to have a protective role against tau pathological hyperphosphorylation in neurons from patients165 and against amyloid-β-induced cell death in embryonic mouse hippocampal neurons in vitro166. Conversely, β-amyloid can induce telomere shortening and inhibit telomerase activity167.

Parkinson’s disease.

Parkinson’s disease is a progressive disorder in which movement is impaired. The disease affects more than 10 million people worldwide (https://www.parkinson.org/Understanding-Parkinsons/Statistics), and age is the main risk factor in both sporadic and familial forms. Senescent astrocytes have been detected in postmortem brain samples from patients with Parkinson’s disease168, and senescence of dopamine neurons has been proposed to contribute to disease pathogenesis169. Although there is no clear evidence of telomere length changes in patients with Parkinson’s disease170, mice with critically short telomeres recapitulate some features of the disease, including poor performance in neuromuscular coordination tests164. Pointing to a causal role of telomere dysfunction in Parkinson’s disease, telomerase activators led to decreased levels of pathological α-synuclein protein and improved motor symptoms in a mouse model of Parkinson’s disease171.

Age-related macular degeneration.

Age-related macular degeneration (AMD) is an eye disease that affects the macula region in the retina and is the most common cause of irreversible blindness in older people worldwide, affecting about 67 million people in Europe alone172. Multiple senescence markers were detected in retinal tissues of AMD animal models and in patients with AMD173.

Different conclusions have been reached regarding the association between leukocyte telomere length and AMD174,175, but a double-blinded study of a small number of patients with early AMD showed that treatment with a telomerase activator significantly improved macular function176.

Reduced fertility.

Currently, up to 25% of couples are affected by infertility (https://www.who.int/reproductivehealth/topics/infertility/burden/en/), and advancing age, especially in females, is associated with reproductive decline. Telomere shortening has been associated with reduced fertility in several ways177–180. Women undergoing in vitro fertilization tend to have shorter leukocyte telomere length than healthy individuals177, and among them, patients with polycystic ovary syndrome with low telomerase activity and short telomeres in granulosa cells, which support oocyte maturation, show an earlier onset of infertility178. Similarly, patients with premature ovarian insufficiency have shorter telomeres and reduced telomerase activity in leukocytes and granulosa cells than healthy individuals179. Short telomeres in human oocytes and polar bodies, which are extruded after meiotic divisions, are associated with aneuploidy in oocytes and early-stage embryos, which is probably due to aberrant chromosome segregation during meiosis180. According to a case report, a woman with dyskeratosis congenita, a telomeropathy associated with a reduced ovarian reserve, responded poorly to hormonal treatment before in vitro fertilization and her oocytes contained critically short telomeres181.

Among males, those with infertility tend to have shorter telomeres in sperm than unaffected men182. Short telomeres have been associated with poor sperm quality in males with normozoosperm183 and with sperm aneuploidy in men with idiopathic infertility184.

Causality of the associations mentioned above is supported by the observation that both sperm and oocytes from mice with critically short telomeres show decreased potential of fertilization and development185. Similar observations have been made in zebrafish and killifish186,187.

Conclusions and therapeutic opportunities.

Here, we summarized age-related conditions that bear an often-unappreciated underlying cause in telomere dysfunction, either in the form of telomere shortening or telomere DNA damage. The identification of a cause can suggest therapeutic options. Preclinical activities in this direction include attempts to counteract telomere shortening or to counteract tDDR activation and cellular senescence. As senotherapies have been reviewed elsewhere188, we will not discuss them here.

To counteract telomere shortening, induction of telomerase activity, either after reactivation of endogenous TERT expression‎83,86 or by its exogenous delivery85,112,164, has been proposed. Because the TERT promoter responds to sex hormones, androgen therapy, based on the clinical use of danazol, a synthetic testosterone, has been part of clinical practice for many years in the treatment of aplastic anaemia with some efficacy83. A natural plant compound named TA-65 has been reported to boost telomerase activity and lengthen telomeres in mice189. Small-molecule inhibitors of PAPD5, a non-canonical poly(A) polymerase that destabilizes TERC RNA, have been shown to rescue TERC levels in induced pluripotent stem cells from patients with dyskeratosis congenita190. The clinical values of these approaches189,190 remain unclear, and they are unlikely to effectively treat patients who carry inactivating genetic mutations in telomerase genes or in genes necessary for its function.

Therapeutic benefits have been observed for AAV-mediated delivery of TERT in animal models of aplastic anaemia, IPF and Alzheimer’s disease164,191. So far, this is the most advanced preclinical therapeutic programme192, although the potential impact of the reported extra-telomeric activities of TERT193 remains to be addressed. Also, this approach cannot benefit patients carrying mutations in genes supporting telomerase activity. Although efficacy has been observed in cardiomyocytes194,195, it remains unclear whether inducing telomerase activity can be beneficial in non-proliferating cells, as in vitro studies indicate that telomerase expression‎ is not able to prevent the accumulation of persistent double-strand breaks at telomeres after exogenous genotoxic insults19,20. Finally, in a clinical context, the use of immunogenic viral vectors such as AAV may reduce the possibility of repeated treatments.

As it is not telomere dysfunction per se that causes cellular senescence or apoptosis but the pathways that it engages, namely tDDR activation, another approach is to blunt the consequences of telomere dysfunction, that is, DNA damage signalling (Box 2). Although it may be dangerous to inhibit DNA damage signalling and repair throughout the genome, an opportunity may lie in the selective DDR inhibition at dysfunctional telomeres. The discovery that DDR activation depends on noncoding RNAs, such as damage-induced long non-coding RNAs (dilncRNA) and DNA damage-response RNAs (DDRNA), generated at exposed DNA ends, including dysfunctional telomeres, make such RNAs attractive targets for potential therapeutic interventions196. Antisense oligonucleotides (ASOs) are an emerging class of drugs targeting RNAs, with eight products presently on the market and many more in advanced clinical trials197. The reported ability of telomeric ASOs (tASOs) to blunt DDR activation specifically at telomeres in vivo in mice72,198,199 and to improve health span and lifespan in a progeria animal model199 provides preliminary but promising bases for their clinical application. An advantage of this approach is its broad activity independent from the genetic defects underlying telomere dysfunction, its ability to act at both critically short and damaged telomeres and in non-proliferating cells, and its nonviral delivery. Limitations of their use may lie in their tissue distribution, the need for safety eval‎uations and their relatively less-studied mechanism of action.

Box 2 |. DDR activation and opportunities for selective DDR inhibition.

DDR activation involves the recognition of DNA damage and critically short or damaged telomeres by sensor proteins such as the MRE1–RAD50–NBS1 (MRN) complex. This complex recruits signalling protein kinases such as ATM and ATR, which phosphorylate the histone variant H2AX (γH2AX once phosphorylated), thereby favouring the recruitment of additional DDR factors such as 53BP1 in the form of DDR foci, named TAFs or TIFs, when colocalizing with telomere markers3,201. Signalling is amplified by additional protein kinases, CHK1 and CHK2, that engage factors such as p53, which control the expression‎ of genes such as the cell cycle inhibitors p21 and p16 that enforce proliferative arrest and cellular senescence202. γH2AX, although necessary, may not be sufficient to induce DDR foci formation, which instead depends also on the synthesis and processing of transcripts generated locally following transcription of the DNA damage site203. Indeed, the MRN complex recruits the RNA polymerase II complex and favours its transcriptional activity by melting DNA ends204, which generates dilncRNA that carry the sequence of the damaged site. Such transcripts can be processed by DROSHA and DICER into shorter DDRNA that can pair with dilncRNA by sequence complementarity. This local network of interacting RNAs retains DDR factors around double-strand breaks in the form of DDR foci, by conferring them with ‘liquid’ properties203–206.

dilncRNA and DDRNA are the only known components that are unique to individual DDR foci, whereas most other DDR protein components are shared among them. Targeting them provides an opportunity to selectively inhibit DDR activation at individual genomic loci. ASOs are established tools to inhibit nuclear RNA functions, with many of them already being approved as medicines197. ASOs against dilncRNA and DDRNA of individual DNA damage sites are able to selectively inhibit DDR activation without interfering with ongoing DDR activation at other untargeted damaged sites within the same nucleus203,206. In the context of telomere biology, dysfunctional telomeres induce the accumulation of telomeric dilncRNA and DDRNA (cumulatively referred here as tncRNA). tncRNA targeting with ASOs (tASOs) selectively inhibited DDR at telomeres, as demonstrated in cultured cells and in mice, where they also reduced markers of cellular senescence and apoptosis, decreased expression‎ of SASP cytokines and improved tissue histopathology, leading to lifespan elongation198,199. Together, these results suggest that they might serve as tDDR inhibitors to determine the contribution of tDDR to physiological and pathological events and to potentially treat tDDR-related diseases.

Of course, the different telomere biology of mice, the most commonly used animal model, with longer telomeres and widespread telomerase expression‎, compared with humans has to be considered when translating any potential therapy to the clinic.

However, for the benefit of patients, both TERT expression‎ and tASO approaches, by acting upstream in the pathological cascade, are expected, and some have demonstrated, to make a promising impact on the many consequences of telomere dysfunction, such as impaired proliferation, inflammation and fibrosis.

Finally, geared with these tools, it is probable that researchers will be able to ascertain and broaden the impact of telomere dysfunction in more diseases.

Acknowledgements

We thank S. Sepe, C. Tripodo and P. Kordowitzki for critically reading the manuscript. Funding in D.J.’s laboratory was provided by grants R01AG 68182-1, the Ted Nash Long Life Foundation and P30DK084567. Funding in J.F.P.’s laboratory was provided by grants 1R01AG 68048-1, 1UG3CA 268103-1, UL1TR 02377-1, the Ted Nash Long Life Foundation and P01 AG 62413-1. F.d’A.d.F.’s laboratory is supported by an ERC advanced grant (TELORNAGING-835103), AIRC-IG (21762), Telethon (GGP17111), AIRC 5×1000 (21091), an ERC PoC grant (FIREQUENCER-875139), Progetti di Ricerca di Interesse Nazionale (PRIN) 2015 “ATR and ATM-mediated control of chromosome integrity and cell plasticity”, Progetti di Ricerca di Interesse Nazionale (PRIN) 2017 “RNA and genome Instability”, Progetto AriSLA 2021 “DDR & ALS”, POR FESR 2014-2020 Regione Lombardia (InterSLA project), FRRB-Fondazione Regionale per la Ricerca Biomedica-under the frame of EJP RD, the European Joint Programme on Rare Diseases with funding from the European Union’s Horizon 2020 research and innovation programme under the EJP RD COFUND-EJP number 825575. Figure 1 was originally created with BioRender.com.

Footnotes

Competing interests

F.R. and F.d’A.d.F. are inventors on the patent applications PCT/EP2013/059753 and PCT/EP2016/068162. J.F.P. and D.J. declare no competing interests. I.F.O.M. has applied for European and US patent applications (EP 13721970.5, US 14/400,131 and 15/476,800), covering the use of antisense oligonucleotides targeting RNA species generated at the site of DNA damage, and for AU, BR, CA, CN, EA, EP, JP, KR, MX and US patent applications (AU2016300141, BR1120180017825, CA 2993128, CN 2016800566045, EA 201890379, EP 16750690.6, JP 2018504223, KR 20187005777, MX/A/2018001126, US 15/748,133 and US 17/065,409), covering the use of antisense oligonucleotides for the treatment of cancer characterized by alternative lengthening of telomeres and non-cancer conditions associated with telomere dysfunction, that list F.d’A.d.F. and F.R.

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