congestive heart failure ( chf ) is a highly prevalent condition affecting more than 15 million patients in europe alone . the incidence and prevalence of chf increases steeply with age and is likely to rise in the next decade due to the increasing average age of the population . advanced age is one of the major risk factors for the development of chf . nevertheless , the susceptibility , age of onset and pace of progression are highly variable . although aging itself does not need to lead to chf , it is likely that age - associated changes lower the threshold for the expression of this syndrome . significant changes in diastolic function , hypertension , atherosclerosis , valve calcifications , senile cardiac amyloid depositions all are associated with aging and an increased risk of the clinical signs and symptoms of chf . the molecular mechanisms involved allow time for accumulated damage to occur and include free radicals , advance glycation end - products , apoptosis and senescence . accumulation of dna damage and telomere attrition can result in an increase in senescent cells in tissue and organs and can subsequently result in decreased function , providing an explanation for the lower threshold to express the clinical manifestation of heart failure . here , we will briefly overview the current knowledge of the cardiac changes associated with aging . one aspect of aging in relation to chf is of particular interest to us , telomere biology . telomeres consist of an evolutionary conserved repetitive nucleotide sequence and are located at the terminal ends of the chromosomes [ 4 , 5 ] . the process of telomere erosion has been put forward as an intracellular counting mechanism that runs parallel with the aging process and the susceptibility to develop chf . at the functional level , there are no age - related changes in cardiac output , end - diastolic or end - systolic volumes or ejection fraction at rest in healthy subjects . however , the myocardial stiffness increases with advancing age , resulting in an elevated left ventricular end - diastolic pressure at rest and with exertion . early diastolic filling is decreased in elderly , a phenomenon seen on echocardiography as a change of the early to late filling velocity ( e / a ratio ) . although the stroke - volume increase during exercise of the young and old is comparable , the old tend to augment stroke volume during exercise more through cardiac dilatation with an increase in end - diastolic volume , whereas the young rely more on increase in the ejection fraction with no cardiac dilatation . during exercise , the older heart rate has a lesser increase in frequency and blood pressure has a greater increase . the difference in heart rate response is associated with a decrease in response to catecholamines and axonal degeneration of sympathetic neurons innervating the atria [ 10 , 11 ] . in addition , the number of pacemaker cells in the sinoatrial node diminishes significantly , from around 50% in youth to less than 30% in elderly . one of the major vascular changes during aging is the decrease in aortic distensibility and decrease in the  windkessel function explaining the frequently observed isolated systolic hypertension in elderly . the mature myocardium constitutes of cardiomyocytes and supporting connective tissue . healthy cardiac tissue is roughly composed of 2025% cardiomyocytes , although this number varies among different species . during aging , the change in morphology is characterized by a loss of myocytes number , with a subsequent hypertrophy of remaining viable myocytes . the mechanism responsible for loss of myocytes is likely to be apoptosis , or programmed cell death . in parallel , there is an increase in collagen content , fibrosis and depositions of  senile cardiac amyloid and lipofuscin [ 1517 ] . prolonged contraction with decreased force of the myofilaments is associated with down - regulation of genes that encode proteins that are involved in contractile activity , such as troponin and myosin forms in the aged heart [ 19 , 20 ] . age - related changes of the mitochondria include a tendency to become larger but less efficient , with a decreased atp production per cell . recent experiments using human left ventricular myocardial cells and carbon - dating techniques have established that dna of cardiomyocytes continues to be synthesized many years after birth , indicating that cells in the human heart do renew well into adulthood . mathematical modeling predicts a ~1% cardiomyocyte renewal rate at the age of 25 and 0.45% at the age of 75 . considering this turnover rate , at the age of 50  years , 55% of the cardiomyocytes remain from the time around birth . there was no significant difference observed in c integration of dna synthesis in cardiomyocytes from subjects with cardiac pathology . interestingly , the c data also indicated a substantially higher renewal rate for non - cardiomyocytes , with a median annual turnover of 18% . unfortunately , data derived from c integration do not allow the identification of the source of new cardiomyocytes . these could be derived either from cardiomyocyte duplication or from some sort of progenitor pool . cells expressing the cardiomyocyte - specific alpha - myosin can be genetically labeled by an inducible recombination technique leading to permanent gfp expression of only cells that expressed alpha - myosin at time of induction . if at a later stage , stem cells ( which initially do not express alpha - myosin ) contribute to cardiomyocyte renewal or regeneration , the percentage of gfp - positive myocytes will decrease . these experiments indicated that stem cells do not replace adult mouse cardiomyocytes during at least 1  year of aging . however , in the setting of myocardial infarction or pressure - overloaded hearts , a significant decrease in percentage of gfp - positive myocytes was observed , suggesting that precursor cells participate in the formation of new cardiomyocytes after injury . the bone marrow is a pool for multiple types of progenitor cells , which are believed to contribute to cardiovascular repair . other possible sources of stem cells that can be stimulated to cardiogenic differentiation are located in adipose tissue or in the bone marrow . a study in young and old bone marrow  derived endothelial progenitor cells ( epcs ) showed that endothelial progenitor cells from 3-month - old donor mice augmented angiogenic capacity in the recipient 18-month - old mice , whereas epcs from 18-month - old donor mice showed no effect . furthermore , young mesenchymal stem cells ( mscs ) showed higher angiogenic response to anoxia than old mscs in vitro , and were more resistant to apoptotic stimuli . infarct size of rats with experimental mi was attenuated after intramyocardial injections of young mscs , whereas injection of old mscs did not lead to any changes . in addition , cardiac function was preserved after mi in all rats that received mscs young , old or a mixture  but the beneficial effect on cardiac function was the largest in rats that received only young mscs . age does not only determine functionality of progenitor cells but is also possibly associated with the number of progenitor cells [ 2729 ] . telomeres are specialized dna structures made up of tandem repeats ( ttaggg in humans ) located at the end of chromosomes [ 4 , 5 ] . telomeres have a critical function as they serve as protective caps , preventing the chromosomal ends to be accidently recognized as dna double strands by the dna damage  repair system , and activation of the p53 or p16 pathway , which eventually leads to senescence or apoptosis . the g - rich strand of the telomere , in conjunction with specialized proteins , form a so - called telomere loop ( t - loop ) concealing the terminal ends of the dna strands ( fig .  1 ) . these specialized proteins include telomeric repeat binding factor 1 ( trf1 ) and 2 ( trf2 ) , which can both bind directly to double - stranded telomere dna . other telomere - associated proteins include the protein protection of telomeres 1 ( pot1 ) , binding directly to single - stranded telomere dna , and repressor activator protein 1 ( rap1 ) , tpp1 and trf1-interacting nuclear factor 2 ( tin2 ) ( fig .  2 ) . telomeres lose 30150 base pairs during each cell division ( also known as the end replication problem ) due to the inability of dna polymerase to fully replicate the 3 end of the dna strand . additional erosion occurs in presence of damaging environmental factors , e.g. , oxidative stress . because telomere length marks the cumulative replicative history and cumulative exposure to environmental factors , it is strongly associated to date of birth ( chronological ) age and is even considered a marker of biological / cellular aging . when the telomere reaches a critical short length , the cell will no longer divide and can become dysfunctional or senescent . on average , cells are estimated to reach senescence after ~50 population doublings . not only telomere length per se but also disruption of the associated telomere - binding proteins responsible for the three - dimensional loop structure can induce chromosomal instability , senescence or apoptosis.fig . 1simplified scheme depicting the structure of the telomere and its location on the chromosome and in the cell . reproduced with permission fig . 2simplified scheme depiction the terminal end of the telomere concealing the terminal single - stranded part with help of the shelterin complex . reproduced with permission   simplified scheme depicting the structure of the telomere and its location on the chromosome and in the cell . reproduced with permission   simplified scheme depiction the terminal end of the telomere concealing the terminal single - stranded part with help of the shelterin complex . reproduced with permission the function of the ribonucleoprotein enzyme telomerase is the elongation of the telomere sequence by addition of nucleotides to their ends . in most mature cells , telomerase activity is nearly undetectable , with exceptions including embryogenic stem cells , germline cells , malignantly transformed cells and some epithelial and lymphoid progenitor cells . telomerase consists of two main components , telomerase rna component ( terc ) and telomerase reverse transcriptase ( tert ) . a third component ( dyskerin ) serves to stabilize the complex ( fig . a less well - understood mechanism through which telomeres can be elongated has been named  alternative lengthening of telomeres ( alt ) . this mechanism is thought to be dependent on the cellular homologous recombination machinery , one of the systems for the reparation of dna double - strand breaks . the alt pathway is not an alternative to telomerase in cells that lack telomerase activity . instead , the alt pathway acts concurrently to telomerase .fig . active telomerase is composed from 2 rna - complexes ( terc ; only 1 depicted ) and 2 telomere - reverse - transcriptase ( terc ; 1 depicted ) stabilized by dyskerin . active telomerase is composed from 2 rna - complexes ( terc ; only 1 depicted ) and 2 telomere - reverse - transcriptase ( terc ; 1 depicted ) stabilized by dyskerin . reproduced with permission   recently , the paradigm that telomeres are transcriptional silent has been broken . telomeric repeat - containing rna ( terra ) is an in length heterogeneous non - coding rna forming an integral component of the telomeric structure [ 32 , 33 ] . as the sequence of terra is complementary to terc , it might be involved in the regulation of telomerase activity or regulation of the dna damage response at short telomeres . several studies have suggested that telomere length can be predicted by the telomere length of the parents . the effect of paternal telomere length is more obvious than that of maternal telomere length . the strength of the association with paternal telomere length is in addition larger for father genome - wide scans have mapped loci associated with telomere length on chromosome 12 , 14 , 18 and 3 near terc ( component of the enzyme telomerase ) . most important are oxidative stress   and factors related to oxidative stress such as smoking   and uv radiation . telomere length has been related to factors predisposing to chf , including hypertension , diabetes mellitus , premature myocardial infarction   and activation of the renin - angiotensin - aldosterone system ( raas ) . the effect of raas inhibition , however , is not clear , since presumably all patients that suffer from chf are taking raas - inhibiting medication , leaving little or no chf patients without raas - inhibiting mediation to serve as valid controls . of course , the effect of raas inhibition could very well be investigated in an experimental heart failure model , but to date no data on this matter have been reported . not surprisingly , patients with chf also have shorter telomeres compared to healthy age- and gender - balanced controls . telomere length has even been associated with the severity of chf symptoms and outcome [ 46 , 47 ] . in addition , worse renal function ( a powerful predictor of outcome in chf and not directly related to vascular function [ 4850 ] ) has been associated with telomere length in subjects with chf [ 51 , 52 ] . it is tempting to speculate this is also due to higher senescence in the kidney and consequently nephron dropout . in apparent healthy elderly , one standard deviation of shorter leukocyte telomere length was associated with 5% reduced left ventricular ejection fraction and telomere length alone accounted for 12% of the observed variability . telomere length is usually measured in leukocytes but has also been evaluated in cardiac tissue from patients with chf . patients with dilated heart failure have ~25% shorter cardiac telomeres compared to healthy controls . in aged diseased hearts characterized by mild hypertrophy and biventricular failure , interestingly , cardiomyocytes with severely shortened telomeres ( < 2.5  kbp ) were positive for p16 , a marker for cellular senescence . the fraction of p16-positive cardiomyocytes was much larger in aged diseased heart compared to non - diseased controls . these findings are consistent with the idea that short telomere length is associated with increased levels of cellular senescence facilitating  if not causing  heart failure . the most prominent question concerning the association between telomere length and heart failure is the causality of this association . does short telomere length directly contribute to the development and progression of heart failure , or does short telomere length itself or the underlying cause of heart failure lead to accelerated telomere shortening ? an attractive explanation could be that telomere dysfunction is a common pathway through which risk factors act and increase cardiomyocyte senescence and dysfunction . the diminished regenerative capacity might also include exhaustion of the progenitor pool with repair capacity [ 5658 ] . fifth - generation telomerase knockout mice have severely reduced telomere length and suffer from severe left ventricular failure , characterized by increased end - diastolic left ventricular pressure , decreased maximally developed left ventricular pressure and disturbed relaxation and contractility very similar to that observed in human dilated cardiomyopathies . on the other hand , stabilizing telomeres by over - expression of trf2 prevents doxorubicin - induced cardiac apoptosis in wild - type mice , but not in telomerase - deficient mice . however , convincing evidence in humans for a causal role is lacking . shorter telomeres could be a consequence or an epiphenomenon rather than a cause of chf . oxidative stress or increased inflammatory status , both related to outcome , could provide a true basis of the development of chf and at the same time explain reduced telomere length . recent clinical chf trials , for example with statins , have not fulfilled their promises in improving prognosis of chf [ 63 , 64 ] . therapeutic strategies to improve myocardial function and outcome in chf are urgently needed , and new medicines are rapidly being introduced [ 6567 ] . telomere biology might be involved in the biology of aging and age - associated pathology . it still needs to be established whether telomere biology is causally involved in the development of chf in humans . large , prospective , longitudinal studies are needed to provide us with more in - depth insights into the nature of the association between telomere length and chf . these studies can clarify whether short telomere length predicts the development of chf  which possibly supports a causal role  or telomere length merely shortens after manifestation of chf . of course , strongest evidence for a causal role would be delivered by interventional studies that demonstrate the cardiac effects of actively altered telomere length . at this time , however , this approach encounters not only several practical obstacles , but also moral objections , since our awareness of all the consequences of telomere length manipulation is surely incomplete . nevertheless , answering the question on causality unambiguously in the near future is essential , as it will allow the development of novel strategies in the treatment and prevention of chf , for example by beneficially modifying stem cells currently used in experimental trials .
during normal aging , the heart undergoes functional , morphological and cellular changes . although aging per se does not lead to the expression of heart failure , it is likely that age - associated changes lower the threshold for the manifestation of signs and symptoms of heart failure . in patients , 
 the susceptibility , age of onset and pace of progression of heart failure are highly variable . 
 the presence of conventional risk factors can not completely explain this variability . 
 accumulation of dna damage and telomere attrition results in an increase in cellular senescence and apoptosis , resulting in a decrease in the number and function of cells , contributing to the overall tissue and organ dysfunction . 
 biological aging , characterized by reduced telomere length , provides an explanation for the highly interindividual variable threshold to express the clinical syndrome of heart failure at some stage during life . in this review 
 , we will elaborate on the current knowledge of aging of the heart , telomere biology and its potential role in the development of heart failure .