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 hereafter) 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.

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 fashion14,15,16.

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 telomeres19,20,21. 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).

Fig. 1: Telomere shortening and damage and their consequences.
figure 1

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 hypersensitive to oxidative DNA damage, a phenomenon recently named TelOxidation22. Oxidative stress reportedly both induces tDD without telomere shortening and accelerates telomere shortening23,24,25,26 by inhibiting telomerase27 and disrupting the recognition by telomere-binding proteins, which contributes to telomere uncapping22,28.

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.

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 tissues20,34,35,36,37. 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.

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

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

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 identified76,77,78. 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 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 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 is characterized by the degeneration of joint cartilage and subchondral bone, and affects more than 30 million adults in the United States ( 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 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 (, 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 ( 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 neurodegeneration158,159, 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 (, 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 (, and advancing age, especially in females, is associated with reproductive decline. Telomere shortening has been associated with reduced fertility in several ways177,178,179,180. 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.

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.