**2. The monographs of aging-associated cardiovascular disease, cancer and**  *Salvia miltiorrhiza*

#### **2.1 Aging-associated cardiovascular disease**

The epidemic of CVDs has taken on a global dimension. CVDs now represent more than 30% of all deaths worldwide. According to the World Health Report, CVDs were responsible for 15 million annual deaths worldwide. Especially in developing countries, 9 million deaths every year while 2 million deaths in economies in transition [10].

CVD is positive related to human's age. By 2030, approximately 20% of the population will be aged 65 or older. At that time, the prevalence of CVD will exponential increase due to the fact that additional 27 million people will have hypertension, 8 million coronary heart disease, 4 million stroke and 3 million heart failure [11]. In this age group, CVDs will result in 40% of all deaths and rank as the leading cause and cost triple payment for treatment [12, 13].

Consistently, researchers have found that many of the factors underlying agerelated changes in the arteries are also implicated in the development of CVD [14]. The incidence and prevalence of common CVDs such as hypertension, atherosclerosis, coronary and cerebral artery disease are increasing at about age 45 in men and age 55 in women [15]. These diseases may develop to increase in the prevalence of congestive heart failure and stroke during aging.

Aging is accompanied by changes in vascular structure and function, especially in the large arteries [16]. The aging cardiovascular tissues are exemplified by pathological alterations including hypertrophy, altered left ventricular (LV) diastolic function, and diminished LV systolic reverse capacity [17], increased arterial stiffness, and impaired endothelial function.

Endothelial dysfunction [18] is one of the major pathologic change of CVDs, besides, increasing intima media thickness, vascular stiffness [19], vesicular smooth muscle cells hypertrophy and proliferation and increasing vessel diameter are related to aging vessels. Impaired endothelial vasodilation is an early sign of arterial aging before the clinical manifestations of vascular dysfunction [20]. As endothelial cells age, they exhibit a reduction in endothelial nitric oxide synthetase (eNOS) activity,

#### *Polyphenols of* Salvia miltiorrhiza *in Aging-Associated Cardiovascular Diseases and Cancer DOI: http://dx.doi.org/10.5772/intechopen.98632*

reducing the abundance of nitric oxide (NO) [21]. NO is a vasodilator produced by endothelial cells, and related to regulate vascular tone, inhibiting vascular inflammation, thrombotic events, and aberrant cellular proliferation [22].

Aging has also a remarkable effect on the heart [23]. The number of cardiac myocytes lessen while heart weight gains with age. The functional cardiac cell continued loss come with the lower regenerative activity from 1% to 0.4% per year of age 20 to 75 years [24]. Most of researches found no obvious difference between male and female in increasing atrial volume [25] and cardiac fibrosis [26]. Although one study of cardiac extracellular matrix proteins found that senior women had a greater amount of collagen and other extracellular matrix proteins in the LV than senior men [27]. A recent work has clearly demonstrated that age-dependent mitochondrial DNA damage is an important substrate underpinning the pathophysiology of cardiac arrhythmias [28]. Another important pathological feature associated with aging is the calcification of aortic and mitral valves which triggers stenosis/insufficiency resulting in cardiac pressure/volume overload [29].

#### **2.2 Cancer**

Cancer is the second leading cause of death globally after ischemic heart disease, accounting for an estimated 9.6 million deaths, or one in six deaths, in 2018 and accounting for nearly 10 million deaths in 2020, but will likely become the first for nearly 18.63 million deaths in 2060 [30, 31]. Lung, prostate, colorectal, stomach and liver cancer are the most common types of cancer in men, while breast, colorectal, lung, cervical and thyroid cancer are the most common among women. It might prevent about one-third to half of cancer death after modifying or avoiding key risk factors and reduce the cancer burden through early detection of cancer. Prevention is the most important and effective long-term strategy for cancer control [32].

Cancer is a multistage process that involves mutational changes and uncontrolled cell proliferation. The etiology of cancer is linked to environmental and genetic inheritance causes. The physical (such as ultraviolet and ionizing radiation), chemical (such as asbestos, components of tobacco smoke, aflatoxin, and arsenic) and biological carcinogens (infections from certain viruses, bacteria, or parasites) may play a role in tumor genesis. The accumulation of molecular damage in DNA, proteins and lipids during the aging progress is also characterized by an increase in intracellular oxidative stress due to the progressive decrease of the intracellular ROS scavenging [33]. Therefore, oxidative stress and the resulting oxidative damage are important contributors to the formation and progression of cancer [34].

#### **2.3 Bioactive components of** *Salvia miltiorrhiza* **(Danshen)**

*Salvia miltiorrhiza* (Danshen) belongs to the *Lamiaceae* family. There are at least 49 diterpenoid quinones, more than 36 hydrophilic phenolic acids, and 23 essential oil constituents have been isolated and identified from Danshen [35]. Our previous population-based studies demonstrated that Danshen is the most common herbal drug used to treat ischemic heart disease [36] and ischemic stroke [37].

The predominant bioactive compounds in Danshen contains two major groups of chemicals [8, 38]. The first group includes lipophilic compounds (Terpenoids) such as tanshinone I, tanshinone IIA, acetyltanshinone IIA, cryptotanshinone, isocryptotanshinone, dihydrotanshinone, 15,16-dihydrotanshinone I, and miltirone (**Figure 1b**). These terpenoids possess a wide range of biological activities including antioxidant

#### **Figure 1.**

*The chemical structures of major (a) lipophilic terpenoids and (b) hydrophilic phenolic acids of Danshen.*

[39], antibacterial [40], anti-inflammatory [41], antiatherogenic, neuroprotective [42], antitumor [43, 44], and antidiabetic [39] effects.

The second group includes the hydrophilic phenolic acids such as caffeic acid, danshensu, salvianolic acid A(SalA), salvianolic acid B(SalB), lithospermic acid and lithospermic acid B (**Figure 1b**). Tanshinones show antibacterial, antioxidant, and antineoplastic activities, whereas phenolic acids possess more antioxidant and anticoagulant activities [45]. The classification of polyphenols mainly includes flavonoids (60%), phenolic acids (30%), and other polyphenols (including stilbenes and lignans) [46]. The main polyphenols in Danshen are phenolic acids (including SalA, SalB, rosmarinic acid, and their derivatives) and flavonoids, which exhibit anti-oxygenation, anti-ischemia–reperfusion injury, anti-thrombosis, anti-tumor, and other therapeutic effects [47]. The main polyphenolic compounds are based on caffeic acid (3,4-dihydroxycinnamic acid), one of the most common phenolic acids, formed from two to four or more caffeic acid units, is one of the most common phenolic acids, frequently exist in fruits, grains, as well as TCM [48].
