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Cardiac ageing: extrinsic and intrinsic
factors in cellular renewal and senescence
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"Applying these integrative analyses to animal models of ageing will be useful for deciphering molecular signals that orchestrate cardiac ageing and understanding how therapeutic strategies can mitigate the decline in healthspan with age."
Functional decline of senescent cardiomyocytes, such as decreased contractility, increased size, mitochondrial dysfunction, and telomere shortening, negatively affects myocardial performance. As these poorly functioning senescent cells accumulate with age, they interfere with intercellular communication, contribute to compromised tissue function, and promote chronic inflammation, leading to cell death and cardiomyocyte loss88,89. Interestingly, inflammation - not telomere shortening - was implicated as the main ageing culprit in a study to identify predictors of longevity in Japanese centenarian individuals90. At the cardiac level, antagonizing the progression of cardiomyocyte senescence is a central theme in approaches to blunt the deleterious consequences of ageing on myocardial structure and function91,92,93.
Conclusions
Ageing and heart disease are the main health-care burdens of industrialized nations in the 21st century. Reductionist research focusing on any single facet of these complex conditions might identify specific components of the whole; however, integrated strategies incorporating epidemiological, environmental, social, and biological studies are increasingly essential to understand the bidirectional extrinsic–intrinsic interactions. From air pollution to nutrition down to molecular signalling and chromatin remodelling, each aspect influences the others. Epidemiologists, public health researchers, clinicians, and basic research scientists need to collaborate to understand and treat heart disease and ageing in a more holistic way to achieve meaningful change. At the cellular and molecular levels, epigenetics performs this function inasmuch as it represents how our chromatin responds to changes in our behaviour and external environment. In this Review, we have examined components of external and internal macro and micro influences on cardiac ageing in the context of how each contributes to cellular and organismal ageing and how they influence each other. Our ability to mitigate cardiac ageing will depend on a far deeper comprehension of the world in which we live, the molecular processes occurring within us, and how these external and internal influences are integrated.
Abstract
Cardiac ageing manifests as a decline in function leading to heart failure. At the cellular level, ageing entails decreased replicative capacity and dysregulation of cellular processes in myocardial and nonmyocyte cells. Various extrinsic parameters, such as lifestyle and environment, integrate important signalling pathways, such as those involving inflammation and oxidative stress, with intrinsic molecular mechanisms underlying resistance versus progression to cellular senescence. Mitigation of cardiac functional decline in an ageing organism requires the activation of enhanced maintenance and reparative capacity, thereby overcoming inherent endogenous limitations to retaining a youthful phenotype. Deciphering the molecular mechanisms underlying dysregulation of cellular function and renewal reveals potential interventional targets to attenuate degenerative processes at the cellular and systemic levels to improve quality of life for our ageing population. In this Review, we discuss the roles of extrinsic and intrinsic factors in cardiac ageing. Animal models of cardiac ageing are summarized, followed by an overview of the current and possible future treatments to mitigate the deleterious effects of cardiac ageing.
Key points
• Ageing is a primary risk factor for cardiovascular disease and mortality.
• The capacity of the adult human heart to maintain function and preserve cellular homeostasis declines with age.
• Extrinsic factors of environment, behaviour, and lifestyle can promote or blunt cellular and molecular cardiac ageing.
• Intrinsic processes that promote cellular ageing, such as inflammation and oxidative stress, exacerbate telomere shortening, chromatin remodelling, and epigenetic drift.
• Cardiovascular ageing is inextricably tied to genetic predisposition and the complex interaction of hereditary influences.
• Promising advances to antagonize myocardial ageing connect external factors with intrinsic molecular mechanisms, enabling interventional strategies on both behavioural and cellular levels.
Sirtuins
NAD-dependent protein deacetylase sirtuins have been extensively studied in association with calorie restriction and longevity, and have been previously reviewed in the context of cardiac disease and ageing229,230,231. Sirtuins comprise seven family members (SIRT1–SIRT7), of which SIRT1–SIRT3, SIRT6, and SIRT7 exert protective effects in the heart229,232. SIRT1, SIRT6, and SIRT7 localize primarily to the nucleus, SIRT2 is cytosolic, and SIRT3–SIRT5 reside in the mitochondria. SIRT1, the most thoroughly characterized sirtuin because of its pro-longevity and cardioprotective activity229,233,234,235,236,237,238, deacetylates histone 3 lysine 9 (H3K9), H3K56, H4K16, and H1K26, as well as many non-histone proteins. Cardiomyocyte-specific knockout of Sirt1 recapitulates an ageing cardiac metabolic phenotype in response to ischaemia–reperfusion239. SIRT2, a cytoplasmic sirtuin, has a role in metabolic processes240 and attenuates cardiac hypertrophy in ageing and angiotensin II-treated mice via deacetylation of serine/threonine-protein kinase STK11 and activation of 5ʹ-AMP-activated protein kinase (AMPK) signalling. Likewise, SIRT2 mediates beneficial effects of metformin, commonly used to treat type 2 diabetes, through downstream AMPK signalling232. Mitochondrial SIRT3–SIRT5, which have been previously reviewed in the context of cardiac disease241,242,243, regulate oxidative stress, mitochondrial metabolic processes, and mitochondrial dynamics, which all mediate CVD and ageing154. Anti-ageing effects of SIRT6 include telomere preservation, DNA repair, enhanced genomic stability, resistance to oxidative stress and inflammation, inhibition of endothelial cell senescence and vascular atherogenesis, and improved glucose metabolism237,244. Severe premature ageing phenotypes, including cardiomyopathy, appear in mice that are deficient in SIRT6 (refs244,245) or SIRT7 (refs246,247,248). Interestingly, SIRT7 is localized primarily to the nucleolus along with nucleostemin (also known as guanine nucleotide-binding protein-like 3) and nucleophosmin, which participate in the cardiac nucleolar stress response and maintenance of youthful phenotypes in CPCs249,250,251,252. SIRT6 and SIRT7 deacetylate nucleophosmin, which becomes increasingly acetylated with cellular senescence as levels of SIRT6 and SIRT7 decline253. Finally, SIRT5 and SIRT7 have been identified as candidate longevity genes in SNP analysis of genes responsive to calorie restriction254.
In summary, the sirtuin family participates in a complex web of intracellular signalling pathways and has multiple roles in cardiac homeostasis, ageing, disease, and metabolism, comprising an array of molecular targets throughout the cell for anti-ageing intervention. Dietary supplements claiming to modulate sirtuin activity are popular products advertised to reverse cellular ageing and improve metabolism. Sirtuins have gained the attention of healthy lifestyle advocates who promote eating foods rich in purported sirtuin activators - the Sirtfood diet - to improve metabolism and overall health. Whether through lifestyle choices or targeted pharmaceuticals, optimizing the activity of specific sirtuins offers the potential to develop therapies that restore a youthful cellular phenotype and facilitate myocardial survival and rejuvenation and to combat ageing and disease.
Lifestyle
Nutrition
Diet has a central role in cardiovascular health, integrating metabolism with cellular function and longevity. Intervention at the nutritional level is a major focus of public health research. For example, the Mediterranean diet, which is rich in fruits, vegetables, nuts, legumes, fish, and unsaturated fats (especially virgin olive oil), has long been associated with anti-ageing and heart-healthy benefits. Molecular mechanisms underlying the beneficial effects of the Mediterranean diet include telomere preservation, anti-inflammatory effects, antioxidant properties, beneficial autophagy, and improved metabolic and lipid profiles114. The PREDIMED-NAVARRA trial115 showed that adherence to the Mediterranean diet for 5 years was correlated with longer LTL in women aged 55–80 years at high risk of CVD. Nutritional genomic approaches applied to the Mediterranean diet identified potentially responsive single nucleotide polymorphisms (SNPs), but prescribing individualized dietary patterns requires further study114,116. Interestingly, the Mediterranean diet might also confer cardioprotective changes at the epigenetic level by modulating DNA methylation in leukocytes117. The omics analysis of cardiac ageing and disease might reveal the molecular underpinnings of the benefits of the Mediterranean diet and the necessary steps for these observations to be applied to promote cardiovascular functional longevity.
Calorie restriction is a dietary strategy thought to improve quality of life and prolong lifespan. Intermittent fasting imparts cardiovascular benefits to fruitflies118,119, rodents120,121,122,123,124,125, and humans126,127,128,129. Purported mechanisms yielding beneficial effects in Drosophila were associated with regulation of circadian clock genes, a chaperonin complex, and the electron transport chain118,119,130. Cardioprotective effects of fasting were observed both before and after myocardial infarction in rats, including higher survival with preservation of cardiac structure and function as well as decreased cell death and increased levels of the pro-survival cytokine adiponectin120,121,122. Likewise, intermittent fasting for 6 weeks was protective against ischaemia–reperfusion injury mediated by protective preconditioning to induce autophagy–lysosome machinery124 as well as tissue-specific redox regulation to protect the heart from oxidative stress123.
Calorie restriction also delays age-related DNA methylation drift, defined as changes in DNA methylation patterns over time, in mice and rhesus monkeys125. The negative correlation between DNA methylation drift and lifespan in mice, monkeys, and humans suggests a molecular mechanism for the beneficial effects of calorie restriction on lifespan and cardiovascular health. However, the potential value of all this experimental research for humans remains debatable, as a systematic literature review concluded that more research is required before recommending fasting as a health intervention126. Nonetheless, the AHA published a scientific statement concluding that intermittent fasting might be useful for weight loss and for lowering triglyceride levels, blood pressure, fasting insulin levels, and insulin resistance128. Consistent with this view, a combined regimen of intermittent fasting and a high-protein, low-calorie diet reduced body weight, improved the blood lipid profile, and reduced arterial stiffness, and this regimen maintained these cardiovascular benefits after 1 year better than the standard heart-healthy diet (<35% of calorie intake as fat, 50–60% of calorie intake as carbohydrates, <200 mg/dl of dietary cholesterol, and 23–30 g per day of fibre, consistent with dietary guidelines of the National Cholesterol Education Program Therapeutic Lifestyles Changes diet) in individuals with obesity127.
Translating these lessons to molecular interventions, calorie restriction mimetics are being developed to simulate the beneficial effects of calorie restriction without requiring reduced food intake131. Calorie restriction and calorie restriction mimetics produce tissue-specific transcriptional effects, with l-carnitine being the only calorie restriction mimetic shown to produce transcriptional changes in the heart similar to those of calorie restriction131. In summary, intermittent fasting seems to have cardioprotective effects in animal models and might improve cardiovascular health in humans, but more rigorous, randomized, controlled clinical trials are necessary before intermittent fasting can be recommended as a medical intervention in the treatment of heart disease129.
Exercise
Physical inactivity is a known risk factor for CVD and premature death132. Exercise confers multiple anti-ageing benefits, particularly in the cardiovascular system, at the systemic and cellular levels133,134. Of note, increased LTL clearly associates with physical activity135,136,137,138,139,140,141,142,143. Even moderate-to-vigorous physical activity is positively associated with LTL and cardiorespiratory fitness144. Molecular mechanisms accounting for the cardioprotective effects of physical exercise might involve increased levels of TERT, telomeric repeat-binding factor 2, and telomerase; activated pro-survival insulin-like growth factor I signalling; and decreased expression of p53 and p16INK4A observed in mice135. Likewise, vasculoprotective effects of voluntary running increase telomerase activity, decrease telomere erosion, and blunt expression of senescence markers in mice135 as well as in human endurance runners136. Even acute exercise influences shelterin complex genes, DNA damage and repair genes, and p38 mitogen-activated protein kinase (MAPK) signalling, indicating an early adaptive response for telomere protection145. Consistent with these findings, high levels of physical activity can confer cellular youthfulness with a 9-year ageing advantage relative to inactivity based on an analysis of National Health and Nutrition Examination Survey (NHANES) data142. Collectively, the benefits of exercise undoubtedly include preserving a youthful phenotype at the cellular and molecular levels, and this preservation can help to slow the degenerative effects of ageing at multiple levels. Clearly, one size does not fit all in terms of exercise regimens for anti-ageing effects. Tailoring fitness recommendations to individuals requires consideration of age, sex, and cultural disparities. Devising research models that address heterogeneity of cardiac ageing at the cellular and molecular levels will be important to understand how best to apply physical activity to diverse patient populations to improve healthspan.
Mental state
Psychological stress, such as chronic stressors from the workplace environment or social context, increases the risk of coronary heart disease146,147,148, possibly through increased inflammation149,150,151. Indeed, the brain–heart interaction is an emerging area of interest in cardiovascular medicine152. One particularly compelling example of the brain–heart pathogenesis link is mental-stress-induced myocardial ischaemia or Takotsubo cardiomyopathy153,154,155. Exercises that confer psychological benefit via stress reduction, such as meditation, mitigate ageing and cardiac disease. In support of meditative therapy, the number of years of regular meditation is significantly inversely correlated with an accelerated epigenetic clock as defined by DNA methylation patterns156. Meditation, yoga, and repetitive prayer empower personal ability to calm the body, termed the relaxation response, which relieves stress157,158. Molecular mechanisms of the relaxation response include upregulation of telomere maintenance and metabolism, whereas inflammation-associated and stress-associated gene expression is downregulated159. Similarly, practitioners of yoga are observed to have longer LTL, higher antioxidant status, and lower levels of the oxidative stress indicators homocysteine and malondialdehyde160. The effect of stress is also observed in murine models, in which psychological stress induced by physical restraint exacerbated vascular senescence and reduced neovascularization in a hindlimb model of ischaemia161. This finding suggested a potential molecular intervention through the dipeptidyl peptidase 4–glucagon-like peptide 1–adiponectin signalling axis161. Sleep deprivation is another aspect of stress affecting the brain–heart axis contributing to cardiac ageing, as investigated in a mouse model of circadian rhythm disruption. Mice expressing mutant Clock, which encodes an important protein for the mechanism of circadian rhythm, developed age-dependent cardiomyopathy162. Finally, the physiological effect of social integration throughout life is emerging as a powerful influence on cardiovascular health and longevity163. Collectively, these studies point to the importance of everyday behaviour and mindset for overall health at the organismal and cellular levels. As public health, clinical, and psychological studies continue to uncover the connections between mental state and cardiovascular health, in vivo and in vitro models deciphering the underlying cellular and molecular mechanisms will be critical for identifying molecular targets to counteract the effects of stress on cardiac ageing.
Telomeres
Telomeres, first described by Hermann Muller in 1938, are the protective, stabilizing ends of eukaryotic chromosomes and are composed of short DNA repeats, telomerase RNA component (TERC), and TERT. Several associated proteins collectively referred to as the shelterin complex contribute to telomere maintenance and stability. Telomeres become shorter with each round of cell division or in response to inflammation and oxidative stress, eventually reaching a critical minimum length, the consequences of which include cell cycle arrest, possible chromosome damage, differentiation, or cellular senescence. Telomere length is perhaps the best-known cellular marker of ageing, with an emerging role in human ageing and disease164. Entire fields of study and industries are based on the premise that telomere length indicates cellular replicative capacity and, by extension, tissue and organismal age. TERT expression, telomerase activity, and telomere length decrease dramatically in postnatal mammalian cardiomyocytes36. Consequently, telomere shortening is primarily driven by inflammation and oxidative stress in the postnatal heart165. The role of telomeres in cardiac disease and ageing, linking inflammation and oxidative stress with telomere attrition, cellular senescence, and death, has been reviewed previously166,167,168,169,170 (Fig. 1).
Telomere length in noncardiac tissue is increasingly being used as a clinical diagnostic tool to assess cardiac age and disease171,172. For example, circulating blood provides an abundant, accessible tissue source for assaying patient telomere length, such that LTL has become a common indicator of systemic ageing in humans and is thought to be a predictive measure of age-associated disease172,173. The first systematic review and meta-analysis of the association between LTL and CVD included 24 studies published up to 2014 and confirmed an inverse relationship between LTL and risk of coronary heart disease174. An analysis of NHANES data revealed that suboptimal cardiovascular health is associated with shorter LTL175 and confirmed that LTL is an indicator of cardiovascular ageing in association with biomarkers of CVD, such as adiposity, insulin resistance, and blood pressure176. Additionally, shortened LTL is a molecular marker of vascular ageing associated with arterial stiffness177 and adverse cardiac outcomes in patients with coronary artery disease172. LTL is a useful but indirect diagnostic measure of cardiac cellular ageing, providing preliminary evidence for how environmental factors affect myocardial function at the cellular and molecular levels. As cellular senescence continues to emerge as a complex and heterogeneous cellular state, closer evaluation of the connection between LTL and myocardial cellular ageing phenotypes will be necessary to establish the clinical relevance and predictive value of LTL as a biomarker for cardiac ageing and risk of CVD.
Genetics
A causal link between genetics in human longevity and progression of cardiac ageing has not been conclusively established. Genetic factors are estimated to underlie one-quarter of the variance in human lifespan, the rest of which is determined by dynamic interactions between genes, environment, lifestyle, and epigenetics178. Animal studies identifying metabolic pathways affecting longevity have provided indications of human genes that influence lifespan and ageing179,180,181,182. Genome-wide association studies (GWAS) have been used to identify novel genetic loci and pathways associated with late-onset CVD, creating new directions of research into mechanisms and potential therapeutic targets for the prevention and treatment of cardiac ageing and disease183,184,185. Whereas so-called good genes are vaguely presumed to predispose individuals to longevity, genetic mutations leading to progeria or Werner syndrome undoubtedly predispose patients to premature ageing186. Indeed, diseases of accelerated ageing often include cardiomyopathy in the phenotype, which provides insights into various cellular and molecular mechanisms underlying shortened lifespan. Mutations in the LMNA gene, which encodes the precursor to lamin-A/C (LMNA), result in an unstable, irregular nuclear envelope, DNA damage, and subsequent premature cell death in childhood progeria (Hutchinson–Gilford progeria syndrome; HGPS). Individuals with this condition have classic ageing phenotypes during childhood and are predisposed to CVD. LMNA cardiomyopathies involve dysregulated gene expression as well as mechanical or conduction defects187. Werner syndrome, another disease of premature ageing, is caused by mutations in the WRN gene, encoding a helicase protein for repairing double-stranded DNA breaks and maintaining genome stability188, and is frequently associated with atherosclerosis189. Animal models of these genetic diseases have been very useful in dissecting molecular mechanisms contributing to cardiac ageing and are discussed in more detail below.
The converse condition to premature ageing is longevity, and longevity-associated candidate genes, such as APOE and FOXO3, continue to be identified in increasingly rigorous genomic analyses190,191. For example, four genetic variants associated with longevity, including candidate loci ABO, APOE–TOMM40, CDKN2B–ANRIL, and SH2B3–ATXN2, were identified using informed GWAS, a novel statistical analysis of human disease genomic data192. The gene encoding the cell-cycle inhibitor cyclin-dependent kinase 4 inhibitor B (CDKN2B; also known as p15INK4B) is located in the same genomic region as the gene encoding the senescence marker p16INK4A, and the ABO blood group locus is associated with cardiovascular disorders193. Other meta-analyses of DNA from elderly individuals of European descent identified 5q33.3 as a novel locus associated with low blood pressure in middle age and a decreased risk of cardiovascular-related death194, whereas a GWAS of Han Chinese centenarian individuals revealed 11 independent, longevity-associated loci, including a novel locus with IL6 as the nearest gene. A comparison of Chinese, European, and US longevity associations identified eight overlapping SNPs and confirmed APOE and 5q33.3 as longevity-associated loci, and this analysis also identified four pathways (carbohydrate metabolism, immune response, MAPK signalling, and calcium signalling) associated with longevity in Han Chinese individuals, suggesting that favourable genotypes mediating defensive mechanisms against toxins, pathogens, or inflammation contribute to longevity in this population195. Although candidate longevity-associated loci are shared by all humans, these studies also highlight the contributions of cultural and environmental factors in the phenotypic manifestation of cardiac health and lifespan.
Not surprisingly, genetic overlap exists between traits of longevity and age-related traits, such as coronary artery disease. Whether the DNA of long-lived individuals lacks disease-associated SNPs, carries beneficial SNPs that promote disease resistance, or contains some combination of both remains unknown. Evidence is accumulating to show that lifespan is influenced by both genetics and modifiable risk factors and that no single genetic profile guarantees longevity. A genome-wide association meta-analysis using parental survival and lifespan data identified two genomic regions associated with longevity as well as specific behaviours and socioeconomic traits affecting life expectancy196, specifically the LPA locus encoding lipoprotein(a), which is known to influence cardiovascular health, and the human leukocyte antigen (HLA) region within the major histocompatibility complex. This meta-analysis showed genetic correlations between complex traits and longevity. Specifically, disease-based measures, such as smoking, diabetes mellitus, and coronary artery disease, showed a negative genetic correlation with lifespan, whereas particular socioeconomic traits, such as education and openness to experience, showed a positive genetic correlation with longevity.
Applying these integrative analyses to animal models of ageing will be useful for deciphering molecular signals that orchestrate cardiac ageing and understanding how therapeutic strategies can mitigate the decline in healthspan with age.
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