the role of biological age in cardiovascular disease

Age is an important prognostic factor in both pri-mary and secondary prevention of coronary heart disease. Age considerations are inherent in sev-eral tools used for risk quantification including the Score, Grace or Framingham Risk Scores. Investiga-tions into molecular mechanisms of regeneration resulted in the introduction of the notion of biologi-cal age, which is a determinant of the regenerative potential of an organism. Defining the biological age consists of the determination of a number of biological age markers including telomeres – com-plexes of nucleic acids and chromatin - stabilising proteins. Cellular senescence induces proportional telomere shortening, a characteristics that helps define the biological age. Other molecular markers that reveal the biological age are cell cycle regulator proteins (p53, p16, p27) and senescence-associated beta-galactosidase (SA-β-gal). Figure 1 illustrates the relationships between the biological age markers.

Biological ageing diminishes the regenerative ca-pacity of the cardiovascular system. A number of cells have been identified that appear to be respon-sible for the regeneration of cardiovascular system components including endothelial progenitor cells (EPC), cardiac progenitor cells (CPC) and smooth muscle progenitor cells (SMPC). Recent research seems to confirm the role of biological age in car-diovascular system regeneration. Kajstura et al. have demonstrated that, from 20 to 100 years of age, the pool of cardiomyocytes is replaced 15 times in women and 11 times in men. Paradoxically, cardiomyocyte turnover increases with the biologi-cal age of the heart, which probably represents a compensatory mechanism for lower regenerative potential of the cells1. Figure 2 presents the role of particular components engaged in cardiovascular system regeneration.

CORRESPONDENCE

Wojciech Wojakowski, MD, PhD, FESC,Third Division of CardiologyMedical University of SilesiaZiołowa 45-47, 40-635 Katowice, Poland

Tel: (48) 604 188669 E-mail: [email protected]

ABBREVIATIONS LIST

AT1R- angiotensin II receptor type 1 AT2R- angiotensin II receptor type 2BMC- bone marrow cellsCAC- coronary artery calcification CHF- chronic heart failureCPC- cardiac progenitor cellsCSC- cardiac stem cellsDM2T- diabetes mellitus type 2EPC- endothelial progenitor cellsHF- heart failurehTERT- human telomerase reverse transcriptase LTL- leukocyte telomere length LTL- shorter leukocyte telomere lengthMI- Myocardial InfarctionP16- p16 proteinP27- p27 proteinP53- p53 proteinP53- p53 proteinPBMCs- peripheral blood mononuclear cellROS- reactive oxygen species SA-β-gal- senescence-associated beta galactosidaseSMPC- smuscle progenitor cellsTRF2- telomeric repeat binding factor 2VSEL- Very small embryonic-like stem cell

ABSTRACT

Age is an important prognostic factor in both primary and secondary prevention of coronary heart disease. The progress in molecular biology resulted in the introduction of the notion of biological age which facilitates the objective estimation of the organism’s regenerative potential. The purpose of this paper is to review the effects of several aspects of biological age on the development and progression of coronary heart disease. The term biological age is defined and its markers are characterised. The influence of risk factors for coronary heart disease and heart failure on biological age is also discussed. Special emphasis is placed on the clinical aspects of cellular senescence in car-diovascular system.

The Role of Biological Age in Cardiovascular Disease

CORONARY HEART DISEASE | REVIEW

Eugeniusz Hrycek, MD & Wojciech Wojakowski, MDThird Division of Cardiology, Medical University of Silesia, Katowice, Poland

Received 14/1/2011, Reviewed 20/1/2011, Accepted 22/1/2011 Key words: senescence, coronary artery disease, telomeresDOI: 10.5083/ejcm.20424884.35

46 EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE VOL I ISSUE III

THE EFFECT OF SOME SELECTED RISK FACTORS FOR CARDIOVASCULAR DISEASE ON BIOLOGICAL AGE

Diabetes mellitus and oxidative stress

Diabetes mellitus affects the prognosis in the primary and secondary prevention of cardiovas-cular disease. Risk quantification scores consider diabetes as a coronary heart disease risk equiv-alent. Salpea et al. demonstrated that type 2 diabetes was associated with shorter leukocyte telomere length (LTL) 2. It was also observed that diabetes accelerated LTL shortening in patients with a history of myocardial infarction3. More-over, an association was shown between the impaired function of circulating endothelial pro-genitor cells (EPCs), impaired neovascularisation process and the activation of the p53 signaling pathway4. From a molecular perspective, diabe-tes generates high levels of oxidative stress re-sulting in cell damage and accelerated ageing.

SHC is an adaptor protein that exists in three isoforms, i.e., p46Shc, p52Shc, and p66Shc. The p66Shc adaptor protein has potential implica-tions for cellular senescence resulting from the induction of mitochondrial oxidation-reduction processes in response to oxidative stress. Re-active oxygen species (ROS) cause damage to nuclear and cytoplasmic structures ultimately resulting in impaired function and apoptosis5,6. Thus, potentially dysfunctional cells exposed to oxidative stress are eliminated. ROS formation associated with SHC expression is paradoxically involved in the process.

47EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE VOL I ISSUE III

THE ROLE OF BIOLOGICAL AGE IN CARDIOVASCULAR DISEASE

Figure 1: Relation between selected markers of cellular senescence

Senescence cells reveal Lower migration and differentiation ability. They are characterized by shorter telomeres, lower telomerase activity and increased expression of cell cycle regulators (p27, p16, p53). These regulators habit the division of potentially insufficient cell. Moreover, the release of senescence-associated beta-galactosidase in the senescence cells is present.Abbreviations: P16- P16 protein, P27- P27 protein, P53- P53 protein

Figure 2: Cardiovascular system regeneration


HEALTHCARE BULLETIN | CORONARY HEART DISEASE

BIOLOGICAL AGE AND SECONDARY PREVENTION OF CORONARY HEART DISEASE

So far we have defined biological age, characterised its standard markers, and discussed the effects of some selected risk factors for coronary heart disease on biological age.

Another patient group comprises individuals involved in the pro-gramme of secondary preventive therapies for coronary heart dis-ease. Telomere shortening seems to be a primary abnormality in the pathogenesis of coronary heart disease25. Reduced LTL is also predictive of increased risk of mortality in patients with stable coro-nary artery 26,27. A prospective study of Farzaneh et al. revealed that LTL in patients with stable coronary heart disease may undergo dy-namic changes, i.e., may increase, decrease or remain unchanged in patients with stable coronary heart disease 28. Advanced biological age is also related to the function of vascular endothelium. Satoh et al. demonstrated EPC telomere erosion in CAD, and protective effect of intensive lipid-lowering therapy on endothelial progeni-tor cell telomeres29. Telomere shortening of autopsised coronary endothelial cells of CAD patients was also confirmed30.

Table 2 presents the role of biological age in the pathogenesis of myocardial infarction, the risk of which is increased in patients with telomere shortening.

Heart failure (HF) is the end-stage of a variety of cardiovascular en-tities. Enhanced cardiomyocyte apoptosis has been implicated as a pathogenic mechanism underlying the development of HF; the process is associated with fibrosis. Table 1 shows selected research reports confirming the role of biological age advancement in HF. Protein p53 seems to act as a key mediator of HF development. Interestingly, it has been hypothesised that telomere shortening might contribute to higher susceptibility to anaemia in HF patients. An association has also been suggested between biological age and HF severity.

LTL has been show to correlate with the results of echocardiograph-ic examinations. LTL was positively associated with left ventricular mass and wall thickness. Thus, LTL might facilitate the prognosis of left ventricular hypertrophy31.

An inverse association of LTL with common carotid artery intima-media thickness32,33 and more extensive coronary artery calcifica-tion (CAC)34 has also been found.

SUMMARY

To summarise, in the future biological age may become an impor-tant therapy target and therapy determinant. Although there are a multitude of risk factors for coronary heart disease, biological age represents their common molecular denominator.

Therefore the p66Shc gene seems to be of important significance in the pathophysiology of ageing and the development of cardio-myopathy7. p66Shc knockout mice display decreased susceptibility to atherosclerotic plaque formation, more efficient endothelium-dependent relaxation, and higher resistance to reperfusion injury associated with oxidative stress 8,9. Inactivation of the p66Shc gene also protects against age-dependent endothelial dysfunction10. Deletion of the p66shc gene in experimental animals with insulin-dependent diabetes mellitus prevents cardiac progenitor cells from telomeric shortening and limits the accumulation of senescence-associated proteins p53 and p16INK4. These findings seem to sug-gest that negative adaptations in the function of cardiac progenitor cells resulting from diabetes-enhanced oxidative stress are among the underlying causes of diabetic cardiomyopathy11. Another re-port indicates a fundamental role of p66Shc in angiotensin II-medi-ated myocardial remodelling12.

Smoking should be emphasised among free-radical generators; the result is oxidative stress. High levels of oxidised-LDL effectively me-diate the ageing process13, and have been shown to inhibit telom-erase activity in endothelial progenitor cells14.

Hypertension

The effect of hypertension on biological age has been documented both in human and animal models. It was demonstrated that leu-kocyte telomere shortening was associated with a higher risk of developing hypertension and, consequently, coronary heart dis-ease15. It was also reported that elevated blood pressure increased p16INK4A expression in rat left ventricular cardiomyocytes and car-diac arteries. The level of hypertension-induced p16INK4A protein expression correlated with the severity of left ventricle fibrosis16. The role of the renin-angiotensin system in biological senescence has also been investigated. Kunieda et al. demonstrated that angio-tensin II induced premature senescence of vascular smooth muscle cells.

The process is probably mediated by angiotensin II receptor type 1 (AT1)17 whereas the cytoprotective angiotensin II receptor type 2 (AT2) mediated antisenescence signalling18. Vasan et al. demon-strated an inversely proportional correlation between renin-to-al-dosterone ratio and LTL19. Interestingly, increased plasma endothe-lin-1 levels associated with telomerase deficiency in mice resulted in hypertension20.

Gender, physical activity, smoking and lipid disturbances

Due to the fact that women show longer telomeres compared to men, a novel endothelium-associated protective estrogen effect on telomeres has been postulated resulting from de novo synthesis of telomeric DNA, enhanced telomerase activity through human telomerase reverse transcriptase (hTERT) phosphorylation and the production of nitric oxide.21

Epidemiological evidence has confirmed that physical activity is as-sociated with reduced risk of cardiovascular disease. Exercise also turns out to act as a telomere protecting factor which was con-firmed by the analysis of telomere biology of circulating leukocytes in human and animal models22,23. Most probably Long- and short-term physical effort up-regulates telomere-stabilising proteins and prevents cardiomyocyte apoptosis 24.

l.p. Author Year Study group Cell population Results

1 Brouilette 2003 203 premature MI patients leukocyte LTL shortening as a risk factor of premature MI45.

2 Fitzpatrick et al.

2007 419 patients leukocyte Increased MI risk in patients (below 74 year old) with shortening of LTL46.

3 Salpea KD et al.

2008 369 subjects (18-28 year old) whose father developed MI

before 55 year of life.

leukocyte Relation between risk of MI in patients from study group with shortening of LTL47.

4 Spyridoou-los Ip

2008 50 MI patints granulocyteleukocyte

BMC

Shortening of telomeres on the bone marrow level in patients after MI48.

5 Zee RY et al. 2009 14 916 healthy subjects leukocyte LTL shortening as a risk factor of premature MI49.

6 Olivieri F. et al.

2009 272 DM2T patients leukocyte MI as an accelerator of LTL shortening in patients with DM2T3.



l.p. Author Year Study group Cell population Results

1 Leri A et al. 1998 Dogs affected by pacing-induced heart failure

cardiomyocytes Increased expression of p53 in experimental HF35.

2 Kajstura et al.

2003 19 patients with idiopathic dilated cardiomyopathy

cardiomyocyte Shortening of telomeres in cardiomyocytes obtained from patients suffering from idiopathic dilated

cardiomyopathy36.

3 Hidemasa Oh et al.

2003 HF patients (qualifed for heart transplantation)

cardiomyocyte Shortening of telomeres and decreased expression of TRF2 in apoptotic cardiomyocytes37.

4 Leri et al. 2003 telomerase knockout mouse

cardiomyocyte Relation between HF and p53 expression38.

5 Urbanek K. et al.

2005 HF patients CSC Shortening of telomeres in CSCs mobilized during ischemic HF39.

6 Newcastle 85+ study

2006 89 patients (85-year old) PBMCs Relation between Ejection Fraction and telomere length40.

7 van der Harst P et al.

2007 620 HF patients leukocyte Shortening of LTL in chronic heart failure patients41.

8 Wong et al. 2009 866 HF patients leukocyte Relation between kidney dysfunction and LTL shortening in chronic heart failure patients42.

9 Das B et al. 2010 Transgenic mice cardiomyocyte Key role of p53 protein in cardiac hypertrophy during HF43.

10 Wong et al. 2010 875 HF patients leukocyte LTL as independent risk factor of anaemia development during chronic heart failure 44.

Table 1: Selected research reports confirming the role of biological age advancement in Heart Failure.

BMC- bone marrow cells CHF- chronic heart failure CSC- cardiac stem cells DM2T- diabetes mellitus type 2 HF- heart failureLTL- leukocyte telomere length MI- Myocardial Infarction P53- p53 protein PBMCs- peripheral blood mononuclear cell TRF2- telomeric repeat binding factor 2

Table 2: The role of biological age in the pathogenesis of myocardial infarction

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the role of biological age in cardiovascular disease

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