Bibliometric analysis of trends in cardiac aging research over the past 20 years

Abstract

Background:

In recent years, many studies have addressed cardiac aging and related diseases. This study aims to understand the research trend of cardiac aging and find new hot issues.

Methods:

We searched the web of science core collection database for articles published between 2003 and 2022 on the topic of “cardiac aging.” Complete information including keywords, publication year, journal title, country, organization, and author were extracted for analysis. The VOS viewer software was used to generate network maps of keywords, countries, institutions, and author relationships for visual network analysis.

Results:

A total of 1002 papers were analyzed in the study. Overall, the number of annual publications on cardiac aging has increased since 2009, and new hot topics are emerging. The top 3 countries with the most publications were the United States (471 articles), China (209 articles) and Italy (101 articles). The University of Washington published the most papers (35 articles). The cluster analysis with author as the keyword found that the connections among different scholars are scattered and clustered in a small range. Network analysis based on keyword co-occurrence and year of publication identified relevant features and trends in cardiac aging research. According to the results of cluster analysis, all the articles are divided into 4 topics: “mechanisms of cardiac aging”, “prevention and treatment of cardiac aging”, “characteristics of cardiac aging”, and “others.” In recent years, the mechanism and treatment of cardiac aging have attracted the most attention. In both studies, animal models are used more often than in human populations. Mitochondrial dysfunction, autophagy and mitochondrial autophagy are hotspots in current research.

Conclusion:

In this study, bibliometric analysis was used to analyze the research trend of cardiac aging in the past 20 years. The mechanism and treatment of cardiac aging are the most concerned contents. Mitochondrial dysfunction, autophagy and mitophagy are the focus of future research on cardiac aging.

1. Introduction

The aging of the population has led to a significant increase in the incidence of age-related diseases, particularly cardiovascular diseases. Cardiovascular disease is a leading cause of morbidity and mortality worldwide, and aging is an important independent risk factor. Cardiac aging is a natural process, accompanied by cardiac hypertrophy and dysfunction of the cardiomyocyte. These pathological changes can cause adverse organ remodeling and ultimately lead to the development of heart failure.^[1,2] As a potential target for preventing cardiovascular disease, including coronary atherosclerotic heart disease, hypertension and heart failure, it is of great significance to explore the potential mechanism of cardiac aging and improve or prevent the occurrence of cardiac aging.

At present, the mechanisms of cardiac aging include oxidative stress-induced damage, mitochondrial dysfunction.^[3–5] In addition, recent studies have also focused on the regulatory effects of autophagy,^[6] noncoding ribonucleic acid and aberrant mechanical or mammalian target of rapamycin (mTOR) signaling on cardiac aging.^[7,8] Cardiac aging has become an important target for the prevention of age-related cardiomyopathy, and potential protective mechanisms vary from early caloric restriction for improving aging progress to resistance to apoptosis signaling molecules to get rid of senescent cells.^[9,10] The number of studies and publications on cardiac aging is increasing and the topics are becoming more diverse. It is necessary to make a quantitative analysis of all the papers in order to understand the status of research on cardiac aging. Bibliometrics can be used to provide an overview of a large number of scholarly articles and to systematically estimate research trends to inform future research.^[11] Bibliometric analysis is based on the core collection database of web of science (WOS), which provides comprehensive publication data and is widely accepted and often used to analyze scientific publications.

The aim of this study was to investigate global trends in cardiac aging research over the past 20 years through bibliometric and visual analysis using VOS viewer software. Our work can help researchers better understand the current situation of cardiac aging research, grasp the research trend, and search for research hot issues.

2. Materials and methods

2.1. Source and extraction of data

In this study, we searched the core collection database of WOS for 1713 articles published between January 1, 2003 and December 31, 2022. The research strategy was as follows: topic sentence (TS) = (“cardiac aging”) or TS= (“cardiac senescence”) or TS= (“myocardial aging”) or TS= (“myocardial senescence”) or TS= (“aging heart”) or TS= (“aged heart”) or TS= (“cardiovascular aging”) or TS= (“cardiovascular senescence”). Excluding non-original articles (n = 419) and articles that did not fit the “cardiac aging” theme (n = 292), 1002 articles were included in the analysis. We analyzed the year of publication, journal, country, institution and author information, and made a comparative analysis of all the topics of the articles in a visual form. This study has been approved by the ethics committee of the 4th Affiliated Hospital of Harbin Medical University.

2.2. Data analysis

All data were imported into VOS viewer v.1.6.16 software (Leiden University, Leiden, Netherlands) for visual analysis and classification and systematic evaluation of publications. Each keyword is represented by a circle, and the diameter of the circle and the size of the label represent the number of occurrences (the same keyword is only counted once if it appears multiple times in a paper). Before VOS viewer analyzes the data, some keywords with similar meanings, such as “senescence”, and “aging,” are combined into 1 keyword. The distance between the 2 keywords indicate the degree of association, and the linked keywords are automatically grouped and clustered using different colors. According to the clustering, all the articles can be summarized into 4 parts: “mechanisms of cardiac aging,” “prevention and treatment of cardiac aging,” “characteristics of cardiac aging”, and “others.” Keywords recorded by the average publication year were used to identify hot topics and research trends in cardiac aging research. The data of literature quantity and topic change with years were imported into Microsoft Excel Office 365 for analysis. The centrality value was calculated using CiteSpace 6.2.R2 software (Drexel University, Philadelphia, USA). All authors independently screened and extracted data for input and collection, and any disagreements were resolved through discussion until consensus was reached.

3. Results

3.1. Research trends of publications

We conducted a comprehensive search of the WOS database of articles on topics related to “cardiac aging” and eventually included 1002 articles meeting the eligibility criteria for the analysis. Table 1 lists the top 10 cited papers in this field, among which 4 papers are highly cited. The 10 papers were cited 6320 times, accounting for 16.27% of the 38,834 citations of all papers. Lakatta, for example, article in Circulation journal called “Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises Part I: aging arteries: a ‘set up’ for vascular disease” was the most cited article (1950 times). By analyzing the number of annual publications over the past 20 years, the research on cardiac aging can be broadly divided into 3 stages. Before 2009, the number of articles was relatively stable, and from 2009 to 2017, the research in this field showed an increasing trend. It is worth noting that the number of annual publications on the subject of “cardiac aging” has exploded in the past 5 years (Fig. 1). Therefore, with the deepening of the research, it is of great significance to summarize and analyze the current results and find new hot spots.

Table 1.

Top 10 cited papers on cardiac aging published from 2003 to 2022.

Rank	Author	Year of publication	Country	Title	Total citations
1	Lakatta, EG et al	2003	USA	Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a “set up” for vascular disease	1950
2	North, BJ et al	2012	USA	The intersection between aging and cardiovascular disease	656
3	Wagers, AJ et al	2013	USA	Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy*	652
4	Dimmeler, S et al	2013	Germany	MicroRNA-34a regulates cardiac aging and function*	588
5	Lakatta, EG	2003	USA	Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part III: cellular and molecular clues to heart and arterial aging	544
6	Yang, BB et al	2017	Canada	Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses*	482
7	Leri, A et al	2004	USA	Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpression	423
8	Strait, JB et al	2012	USA	Aging-associated cardiovascular changes and their relationship to heart failure	369
9	Matoba, S et al	2013	Japan	Cytosolic p53 inhibits parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart	351
10	Zheng, XF et al	2019	Canada	Circular RNA in cardiovascular disease*	305

RNA = ribonucleic acid.

^*Stands for highly cited paper.

Figure 1.

Number of annual publications on cardiac aging from 2003 to 2022.

3.2. Distributions of countries and institutions

A total of 59 countries and 1319 institutions contributed to the publication of 1002 articles. The top 10 countries and institutions that publish the most papers are shown in Table 2. Three countries published more than 100 articles: the United States, China and Italy, which contributed 471, 209 and 101 papers respectively. Eight of the top 10 most-published institutions are from the United States, with 1 each from China and Canada. Notably, papers from Harvard University and the NIH National Institute on Aging were cited more than 100 times on average. Centrality is used to evaluate the position of nodes such as keywords, countries, or institutions in the network. Higher centrality reflects greater impact. The centrality value of the United States is 0.83, which is significantly higher than that of other countries, which also means that the United States is at the center of research on cardiac aging. It is followed by Germany and France with Centrality value of 0.22 and 0.15 respectively. Although China and Italy published more articles, the centrality value was still low, indicating the need to increase influence by improving the quality of papers, as increasing the number of publications is not enough. In addition, Harvard University in the United States has the highest centrality value (0.17). The centrality value of other institutions is low, which may be related to the large number and relatively dispersed agencies.

Table 2.

Top 10 contributors in terms of country and institution of publications.

Rank	Country	Number (% of total)	Centrality	Average citation	Institution	Number (% of total)	Centrality	Average citation
1	USA	471 (47.01)	0.83	49.36	University of Washington	35 (3.49)	0.09	75.06
2	China	209 (20.86)	0.07	23.67	Harvard University	26 (2.59)	0.17	124.42
3	Italy	101 (10.08)	0.09	39.97	University of Wyoming	23 (2.30)	0.00	51.56
4	Germany	73 (7.29)	0.22	42.11	University of California San Diego	21 (2.10)	0.02	34.33
5	Canada	52 (5.19)	0.00	43.25	Fudan University	20 (2.00)	0.01	43.8
6	England	50 (4.99)	0.06	25.16	Dalhousie University	20 (2.00)	0.00	30.7
7	Japan	47 (4.69)	0.01	42.06	Baylor College of Medicine	19 (1.90)	0.00	38.21
8	France	41 (4.09)	0.15	48.05	University of Florida	16 (1.60)	0.01	70.13
9	Spain	31 (3.09)	0.09	27.84	San Diego State University	15 (1.50)	0.01	70.8
10	Netherlands	31 (3.09)	0.02	49.51	NIH National Institute on Aging	15 (1.50)	0.01	120.67

Figure 2A also shows the links between countries with more than 5 articles published. The association between them shows regional clustering. Consistent with the results of the central value analysis, the United States was strongly associated with a number of countries in the study of cardiac aging. Countries such as Belgium, France and the United States are among the earliest to explore the field of cardiac aging, while Argentina, China, Egypt, Austria and Iran have focused on this topic in recent years (Fig. 2B). Similarly, while a number of institutions in the United States are more closely connected and centrally located and have explored the field early, it is worth noting that the number of institutions in China has increased rapidly in recent years (Fig. 3).

Figure 2.

(A) Network visualization of countries, (B) overlay visualization of countries.

Figure 3.

(A) Network visualization of institutions, (B) overlay visualization of institutions.

3.3. Distributions of journals and authors

Over the past 20 years, a total of 200 journals have published papers on the topic of cardiac aging. Table 3 lists the top 10 most-published journals, which together published 295 articles on the topic of “cardiac aging,” representing 29.44%. The Journal that published the most articles was the American Journal of Physiology Heart and Circulatory Physiology with 49 articles. Combined with the results of average citation frequency, Circulation Research had the highest average citation frequency of each article (115.2 times per article). And the average citation frequency of articles is roughly proportional to the journal’s impact factor. The top 10 active authors in total published papers are shown in Table 4. Ren, Jun and Lakatta, Edward G were the authors with the most publications (n = 19) and the most cited times (3576 times), respectively. Most of the top 10 authors are from the United States. In addition, in order to have a more intuitive understanding of the cooperative relationship between different authors, cluster analysis is conducted for authors who published more than 5 articles in Figure 4. Each circle represents 1 author, and the lines between the circles represent the relationship between authors. It can be seen from the figure that the connections among different scholars are scattered and clustered in a small range.

Table 3.

The top 10 journals in terms of the number of papers published on cardiac aging.

Rank	Journal	Number (% of total)	Impact factor 2022	JCR	Average citations
1	American Journal of Physiology Heart and Circulatory Physiology	49 (4.89)	5.125	Q1	45.29
2	Journal of Molecular and Cellular Cardiology	37 (3.69)	5.763	Q2	46.38
3	Circulation Research	35 (3.49)	23.213	Q1	115.20
4	Experimental Gerontology	35 (3.49)	4.253	Q2	21.83
5	Aging-Us	34 (3.39)	5.955	Q2	19.35
6	Aging Cell	26 (2.59)	11.005	Q1	60.81
7	Cardiovascular Research	23 (2.30)	13.081	Q1	55.74
8	Oxidative Medicine and Cellular Longevity	19 (1.90)	7.310	Q2	34.32
9	Plos One	19 (1.90)	3.752	Q2	27.42
10	Journals of Gerontology Series A Biological Sciences and Medical Sciences	18 (1.80)	6.591	Q1	26.44

JCR = journal citation reports.

Table 4.

The top 10 authors for the number of articles published on cardiac aging.

Rank	Author	Country	Number (% of total)	Total citations	Average citation
1	Ren, Jun	China	19 (1.90)	1076	56.63
2	Lindsey, Merry L	USA	14 (1.40)	874	62.43
3	Howlett, Susan E	Canada	14 (1.40)	510	36.43
4	Bodmer, Rolf	USA	13 (1.30)	504	38.77
5	Rabinovitch, Peter S	USA	13 (1.30)	1709	131.46
6	Cieslik, Katarzyna A	USA	12 (1.20)	375	31.25
7	M. L. Entman	USA	12 (1.20)	359	29.92
8	Trial, JoAnn	USA	11 (1.10)	354	32.18
9	Lakatta, Edward G	USA	11 (1.10)	3576	325.09
10	Anversa, Piero	USA	10 (1.00)	1631	163.10

Figure 4.

Network map of authors in cardiac aging.

3.4. Distributions of hotspots and frontiers

As the condensed and core of the paper, keywords are helpful to comprehensively understand the general situation and trends of the research, and better search for undiscovered or hot issues in the research field. VOS viewer was used to visually analyze the keywords of 1002 articles to help find the research direction and hot issues in the field of cardiac aging. Of the 2605 keywords, 44 were used ≥ 15 times in the titles and abstracts of all the articles. The most commonly used terms were “aging” (405 times), “cardiac aging” (146 times), “oxidative stress” (118 times), “heart failure” (102 times), and “cardiovascular disease” (83 times). Figure 5 shows the network and overlay visualizations of keywords. As shown in Figure 5A, they are divided into 4 clusters according to the interrelationship between keywords: red cluster is mainly related to “mechanisms of cardiac aging,” green cluster represents “prevention and treatment of cardiac aging,” blue cluster represents “characteristics of cardiac aging,” and yellow cluster represents other aspects of cardiac aging research, such as myocardial age-related diseases and risk factors. In the cluster of “mechanisms of cardiac aging,” the most used keywords were “oxidative stress” (118 times), “mitochondrial” (63 times), “autophagy” (59 times), “ischemia reperfusion injury” (31 times) and “mitophagy” (24 times). In terms of “prevention and treatment of cardiac aging,” the keywords “gene expression” (49 times), “stem cells” (30 times), “micro-ribonucleic acid (RNA)” (20 times), “life-span” (19 times) and “metabolism” (19 times) appeared more frequently. The most frequently used keywords for “characteristics of cardiac aging” were “heart failure” (102 times), “cardiac hypertrophy” (37 times) and “fibrosis” (33 times). In terms of “others,” “cardiovascular diseases” (83 times), “myocardial infarction” (46 times), “telomeres” (22 times), and “sex differences” (17 times) appeared more frequently.

Figure 5.

Co-occurrence analysis based on keywords in cardiac aging studies. (A) Network visualization of keywords, (B) overlay visualization of keywords.

The VOS viewer applies color to keywords according to the year they appear in the literature. Keywords in blue appeared early followed by green and yellow colors, which appeared later. We noticed that in the early studies, more attention was paid to myocardial changes in the aging process and related diseases, as well as the mechanism of ischemia reperfusion injury and oxidative stress on cardiac aging. With the deepening of the research, more hot words gradually emerged. At present, more attention is paid to autophagy, mitophagy, inflammation, fibrosis, microRNA, and metabolism etc (Fig. 5B).

In order to further grasp the research trend, we carry out dynamic analysis of the number of articles under different clusters. All articles were divided into 4 categories: “mechanisms of cardiac aging” (249 papers), “prevention and treatment of cardiac aging” (288 papers), “characteristics of cardiac aging” (265 papers), and “others” (200 papers). Figure 6 shows how the number of articles published in different categories changed from year to year. As can be seen from the figure, articles before 2012 are mainly related to the characteristics of cardiac aging. With the attention paid to cardiac aging in recent 10 years, the number of articles is increasing, among which, the number of articles on the mechanism of cardiac aging, as well as prevention and treatment of cardiac aging continues to increase. In order to further explore the mechanism and prevention of cardiac aging and find new hot issues, we summarized the keywords under the 2 clusters and carried out visual analysis.

Figure 6.

Annual research trends in publications on cardiac aging over the past 20 years.

Of the 537 papers on mechanisms and prevention of cardiac aging, 264 used mouse as animal model, 31 involved human studies, and a few others used fruit flies, rabbits or monkeys as models. A total of 1476 keywords were included in the articles related to the mechanism and prevention of cardiac aging, among which 78 keywords were used more than 5 times. We removed “aging” and “cardiac aging” in order to find the content that the authors paid more attention to in this topic. As shown in Figure 7, “oxidative stress” was the keyword that appeared most frequently (85 times), and its related “insulin” (5 times), “growth faction-1” (8 times) and “nitric oxide” (6 times) were found to be related to the regulation of oxidative stress at an early stage. Subsequently, many studies have focused on “cardiac hypertrophy” (20 times), “cardiac remodeling” (8 times), and “cardiac dysfunction” (17 times), including “heart failure” (50 times), associated with cardiac aging. Over the same period, there have been many efforts to slow the aging of the heart, such as “rapamycin” (9 times), “sirtuins” (14 times), “resveratrol” (5 times), “stem cells” (18 times), and “caloric restriction” (26 times). It is worth noting that with the deepening of research, more new mechanisms involved in the regulation of myocardial aging are gradually recognized. For example, terms related to “mitochondrial” (35 times), “autophagy” (44 times), “mitophagy” (16 times), “doxorubicin” (11 times), “microRNA” (13 times), “mTOR” (6 times) and “inflammation” (25 times) in the current study. In addition, studies of “parkin” (7 times), “Nrf2” (5 times), “melatonin” (5 times), and klotho (5 times) in protecting the heart from aging are beginning to emerge. The new content extended from these keywords should be the hot topic that needs most attention at present and future research.

Figure 7.

Overlay visualization of keywords in the topics of “mechanisms of cardiac aging” and “prevention and treatment of cardiac aging.”

4. Discussion

In this study, literature metrology and visualization analysis were used to summarize the articles related to cardiac aging in the past 20 years. As a hot topic, the number of articles on cardiac aging has been increasing, and it has been widely studied by scholars from many countries and institutions. Our analysis results are helpful for readers to understand the current research status of cardiac aging and provide new research directions and ideas for researchers.

Since 2009, the number of articles on cardiac aging has increased. Especially in the past 5 years, the annual publication volume of articles on this topic has increased rapidly, with 105 articles published in 2021. Moreover, by analyzing the citation frequency of articles and journals, it is found that there are many highly cited papers on this topic, and the journal citation reports partition of the top 10 journals with the number of published articles is Q1 or Q2. This shows that the research on the theme of cardiac aging is of great significance, and there will be a wider space for development in the future. We further analyzed the literature sources and found that the United States, China and Italy contributed the most literature. It is worth noting that the United States has the highest centrality value and occupies a central position in relations with other countries, and many high-producing institutions and scholars are from the United States, indicating that great achievements have been made in this field. But we were pleased to find that there are a number of emerging forces in the field of cardiac aging. For example, in recent years, China, Argentina, Egypt, Austria, and Iran have paid more attention to this topic. In addition, many Chinese institutions have also made a lot of efforts in this field. However, cluster analysis with author as the keyword found that the links between different scholars were scattered. Close exchanges between institutions and scholars are conducive to the deepening and development of research, so it is necessary to strengthen the cooperation between different scholars in the future.

According to the results of keyword cluster analysis, we divided the research on cardiac aging into 4 different tops, including “mechanisms of cardiac aging,” “prevention and treatment of cardiac aging,” “characteristics of cardiac aging”, and “others.” From the analysis of the number of published papers on various topics in different years, it can be seen that the number of researches on the mechanism of cardiac aging and its prevention and treatment has increased significantly, which is the most concerned topic in this field. With the progress of science and technology, excavate the potential of cardiac aging mechanism to slow the aging progress will be the future research direction. Further analysis of studies related to the mechanism and prevention or treatment of cardiac aging revealed that 38.96% and 57.99% of studies were based on mouse models, respectively, while few studies focused on human populations (6.43% and 5.21%, respectively). Since mouses have a higher metabolic rate than humans, and have less genetic diversity than humans due to inbreeding, more importantly, humans will encounter various risk factors, which also accelerate the progression of cardiac aging. The aim of the research is to promote human health, so there will be broader scope for future research on human cardiac aging.

A overlay visualization analysis of the keywords under the themes of mechanism, prevention and treatment of cardiac aging shows that “oxidative stress” is the most frequent keyword. Oxidative stress is 1 of the most important mechanisms of aging. Studies have shown increased expression of genes associated with oxidase production in animal models of aging,^[12] along with an overall decrease in antioxidant enzyme activity. This imbalance in oxidative stress regulation increases reactive oxygen species (ROS) production and accelerates cell aging by inducing intracellular signal-mediated apoptosis.^[13] Earlier studies have shown that insulin/insulin-like growth factor-1 (IGF-1) can stimulate ROS production and participate in cardiac aging through the IGF-1/IGF-1 receptor signaling pathway.^[14] At the same time we also observe the study of “gene expression” and “proteomics.” During the aging process, cells are subjected to various stresses, resulting in changes in gene expression levels. Most of them affect genes encoding proteins involved in oxidative phosphorylation and substrate metabolism. Analysis of gene and protein expression levels can help to explain the process and mechanism of cardiac aging. As previously mentioned, the expression of mitochondria-related genes is altered differently in the aging heart,^[15] leading to increased ROS production in cardiomyocytes and further increasing the sensitivity of aging heart muscle to oxidative stress.^[12] The expression level of sirtuin-3 (SIRT3) gene in the myocardium of aging mice is significantly decreased, and the loss of SIRT3 leads to increased sensitivity of cardiomyocytes to Ca²⁺, mitochondrial swelling, and ultimately accelerated cardiomyocyte aging.^[16] Similarly, Cisd2, as an evolutionally conserved gene that regulates lifespan,^[17] is reduced in expression during aging, leading to mitochondrial dysfunction, disruption of cytoplasmic Ca²⁺ homeostasis, increased ROS production, and dysautophagy.^[18] In addition, oxidized and ubiquitinated proteins accumulate in the heart of aging rats, leading to changes in protease activity,^[19] and the disruption of this protein stability exacerbates cardiovascular aging.

Subsequently, new mechanisms of cardiac aging were explored. Aging is associated with chronic low-grade aseptic inflammation or inflammation. Altered immune cell phenotypes and inflammation are also evident in aging hearts. In 1 study, T cells in older mice induced mild cardiac dysfunction in young mice,^[20] and T-cell-specific deficiency of mitochondrial transcription factor A promoted chronic inflammation and accelerated aging of the cardiovascular system.^[21] Heart failure in the elderly is characterized by a heart failure with preserved ejection fraction, which is also considered an inflammatory multi-organ syndrome.^[22] One study showed that elderly people with elevated levels of inflammatory biomarkers were at significantly higher risk of heart failure with preserved ejection fraction than those with normal levels of inflammatory biomarkers.^[23] Telomeres are short repeated sequences of deoxyribonucleic acid at the ends of linear chromosomes in eukaryotic cells that get shorter as cells divide. Telomeres are susceptible to oxidative stress,^[24] and Anderson et al^[25] demonstrated that telomere damage causes cardiomyocyte senescence. noncoding RNAs are functional RNAs that do not encode proteins, and studies have shown that microRNAs have a powerful regulatory role in cardiac aging.^[26] For example, transforming growth factor-β induces H4K20me3 deletion in elderly mice through miR-29, which triggers cellular senescence and cardiac senescence.^[27]

In recent studies, more attention has been paid to the keywords “mitochondrial” and “autophagy.” Mitochondria are abundant in cardiomyocytes and the integrity of mitochondrial structure plays an important role in energy metabolism of cardiomyocytes.^[28] The aging process itself can lead to changes in the structure and number of mitochondria, resulting in decreased activity of the respiratory chain complex and dysfunction of mitochondrial energy transport. This age-related mitochondrial dysfunction can lead to increased ROS production, Ca²⁺ homeostasis disturbances and quality control deficiencies, which in turn contribute to cardiac aging.^[29] Autophagy is a catabolic process that eliminates macromolecules and damaged organelles via the lysosomal pathway.^[30] Mitochondria are in dynamic change and their homeostasis is regulated by mitosis phagocytosis. Mitotic phagocytosis is a selective degradation process of damaged or stressed mitochondria and therefore has an important protective effect on aging myocardium. There is evidence that the reduction of autophagy or mitophagy accelerates the aging process and adversely affects the heart.^[31,32] The aging process is accompanied by a decrease in mitochondrial autophagy, which involves a variety of molecular regulatory pathways, such as mTOR, adenosine monophosphate-activated protein kinase (AMPK), sirtuins and ROS. Reduced autophagy will inevitably lead to increased cell damage. The mTOR signaling pathway is a key factor in protein synthesis and cell metabolism, and is involved in the regulation of aging by regulating metabolic adaptation, autophagy and mitochondrial biogenesis. Older mice show higher mTOR activity in the heart than younger mice, which leads to inhibition of autophagy and causes cardiovascular dysfunction.^[33] The regulation of “sirtuins” against cardiac aging dysfunction is also a hot issue that needs attention. Sirtuins are a family of enzymes composed of nicotinamide adenine dinucleotide-dependent histone/protein deacetylases, which can regulate cell stress, metabolism, aging, and apoptosis, and play a role in anti-stress and delaying cell senescence. Many studies have shown that sirtuins regulate autophagy and longevity. During cardiac aging, the expression and activity of sirtuins gradually decrease, leading to a decrease in the heart’s resistance to disease, and their up-regulation is thought to be related to the beneficial effects of caloric restriction on antiaging.^[34]

Earlier studies in slowing heart aging focused on caloric restriction. As a dietary pattern that permanently or regularly reduces caloric intake and reliably extends healthy life span.^[35] caloric restriction plays an important regulatory role in reducing oxidative stress damage and inflammation, improving telomerase activity, activating autophagy, and improving mitochondrial dysfunction.^[36,37] Similarly, exercise may increase antioxidant capacity by increasing reactive oxygen scavenging enzymes, while acting as an induced form of physiological stress may slow or reverse the process of cardiac aging.^[38]

Interventions such as enhancement of autophagy and improvement of mitochondrial dysfunction can delay or even reverse the process of cardiac aging.^[39,40] Therefore, as potential therapeutic targets, they are also the most important issues in the treatment of cardiac aging. A recent study showed that rapamycin can enhance autophagy and in turn reduces myocardial aging.^[8,41] Spermidine was found in a study to improve cardiomyocyte aging by activating sirtuins signaling pathway, thereby enhancing mitochondrial biogenesis and function, which provided a new therapeutic strategy to combat cardiac aging and prevent age-related cardiovascular diseases.^[42] At the same time, we noticed that doxorubicin was also a hot word. With advances in cancer treatment in recent years, long-term adverse effects associated with cancer treatment have become increasingly apparent. One of the adverse effects is therapeutic aging, including damage to heart function. Cancer chemotherapy, such as anthracycline doxorubicin, interferes with mitochondrial structure and function of tumor cells. Therefore, it will be of great value to search for interventions to slow down aging in cancer treatment. Exosomes derived from bone marrow mesenchymal stem cells treated with hypoxia have been used to inhibit doxorubicin induced cardiac senescence.^[43] In addition, radiotherapy also causes cells to express senescent phenotypes. Senescence-associated secretory phenotype (SASP) activation is a dynamic, cell type-dependent process that can affect the surrounding cellular microenvironment and lead to cardiac aging. Targeting SASP is another strategy for regulating aging phenotypes, reducing inflammation, and improving vascular function after cancer treatment. Senescence-mitophagy associated long noncoding RNA overexpressed hearts showed a significant increase in SASP compared with healthy hearts, suggesting that noncoding RNA has therapeutic potential in treating cardiac aging.^[44] “Parkin” and “melatonin” also play a role in improving cardiac aging by improving mitochondrial autophagy and reducing oxidative stress damage and inflammation.^[45,46]

There is evidence to support regeneration of aging myocardium, and apoptotic heart cells can be replaced by new cells derived from cardiac stem cells/progenitor cells.^[47] Therefore, CPCs show potential therapeutic value in repairing damaged senescent cardiomyocytes. Although studies have shown that transplanting CPCs in aging rats improves heart function,^[48] the safety of cell therapy in preventing and treating cardiac aging remains controversial, and more research should be conducted to address this in the future.

In other aspects of cardiac aging research, “cardiac hypertrophy” and “cardiac remodeling” are also topics of concern. Oxidative stress and changes in energy metabolism during aging trigger hypertrophy and pro-fibrosis signaling cascades, accompanied by increased intimal thickness and collagen deposition, which thickens and hardens arterial walls and aggravates cardiac afterload. Aging hearts are characterized by myocardial hypertrophy, interstitial fibrosis and impaired systolic function, increasing the incidence of heart failure.^[49] AMPK is associated with the regulation of SIRT and mTOR, and its deficiency promotes age-related myocardial hypertrophy.^[50] AMPK is the primary target of metformin, which activates AMPK to protect the heart from age-induced cardiac hypertrophy.^[51] SIRT3, as a mitochondrial sirtuin subtype, can stimulate oxidative phosphorylation through direct deacetylation of electron transport chain complexes. SIRT3 overexpression promotes autophagy and reduces myocardial hypertrophy.^[52] Several natural and synthetic acetyl transferase p300 small-molecule inhibitors, including curcumin and the p300 activity regulator resveratrol, have also been used to prevent or treat adverse remodeling of aging myocardium.^[53] Rapamycin and the ketogenic diet also play a positive role in improving age-induced ventricular remodeling.^[54,55]

In this study, we conducted a multi-angle analysis of articles on the topic of cardiac aging over the past 20 years, and summarized the research contents from different perspectives according to time nodes. Our work can help researchers better understand the current situation of cardiac aging research, grasp the research trend, and search for research hot issues. At the same time, we found that there are still many problems to be solved in the study of cardiac aging, which mainly focus on the epigenetic changes of aging myocardium, the study of cardiac aging in the process of tumor therapy, the application of stem cell therapy in cardiac aging, the regulation of aging by targeting immune cells and other aging mechanisms and measures to delay cardiac aging. How to better serve human beings with the research results, so as to delay the effects of heart aging and related diseases will be of great significance. There are still some limitations in this study. First, we used WOS for literature search, which may have missed some papers indexed by other databases. Second, searches based on titles and abstracts mean that a small number of manuscripts dealing with aspects of cardiac aging may not be identified.

5. Conclusion

This study analyzed the global research trend of cardiac aging in the past 20 years. The results show that the research on cardiac aging is attracting extensive attention from scholars from many countries and institutions. Currently, most studies focus on exploring the mechanism and treatment of cardiac aging. “mitochondrial dysfunction,” “autophagy” and “mitophagy” are hot words in current research. In the future, it will be of great significance to apply the research results to delay the aging of human heart.

Acknowledgements

The authors extend their gratitude to the participants involved in this study.

Author contributions

Data curation: Yan Hao, Sally A Huber.

Formal analysis: Yan Hao, Bohan Li.

Funding acquisition: Wei Liu.

Project administration: Wei Liu.

Software: Yan Hao, Bohan Li.

Supervision: Sally A Huber, Wei Liu.

Visualization: Yan Hao.

Writing – original draft: Yan Hao.

Writing – review & editing: Sally A Huber, Wei Liu.