Effects of Caloric Restriction on Cardiovascular Aging in Non-human Primates and Humans

Synopsis

Approximately one in three Americans has some form of cardiovascular disease (CVD), accounting for one of every 2.8 deaths in the United States in 2004. Two of the major risk factors for CVD are advancing age and obesity. An intervention able to positively impact both aging and obesity, such as caloric restriction (CR), may prove extremely useful in the fight against CVD. CR is the only environmental or lifestyle intervention that has repeatedly been shown to increase maximum life span and to retard aging in laboratory rodents. In this article, we review evidence that CR in nonhuman primates and humans has a positive effect on risk factors for CVD.

Cardiovascular Disease

Heart disease is the leading cause of death in the United States¹, and has been for nearly a century², while stroke is the number three cause of death³. Approximately 80 million, or one in three, American adults have some form of cardiovascular disease (CVD). In 2004, one of every 2.8 deaths in the United States was attributable to CVD¹. CVD claims more lives each year than cancer, chronic lower respiratory diseases, accidents, and diabetes mellitus combined⁴. As the population ages and the epidemic of obesity continues, the number of people living with heart disease also continues to rise, and an increasing number of younger individuals are being diagnosed with CVD^{5, 6}.

Heart Disease and Aging

Due in large part to a 20-year increase in average life span during the second half of the 20^th century, the median age of the world’s population is increasing, and this trend is expected to continue worldwide, with average life span rising another 10 years by the year 2050⁷. In the United States, the proportion of the population over 65 years of age is projected to increase from 12.4% in 2000 to 19.6% in 2030⁸. The number of persons over 65 years of age is expected to increase from approximately 35 million in the year 2000 to an estimated 71 million in the year 2030⁸, and the number of persons over 80 years of age is expected to increase from 9.3 million in the year 2000 to 19.5 million in the year 2030⁸. Since age is the major risk factor for CVD¹, deaths due to CVD are expected to increase substantially. In addition to the actual increase in prevalence of heart diseases with aging, several major risk factors for CVD (i.e. blood lipids, blood pressure, hemostatic factors, inflammatory markers, and endothelial function) increase with age⁹. Given the substantial morbidity and mortality associated with CVD, in addition to its economic impact on the individual, the family, the nation, and the world, identification of interventions that can successfully decrease the incidence and/or severity of CVD would be expected to have a major impact on global health and related health care costs.

Cardiovascular Disease and Obesity

The link between obesity and CVD has been clearly established. Left ventricular hypertrophy, hypertension, diastolic dysfunction, poor cardiac contractility, and dyslipidemia are all recognized cardiovascular complications of obesity^{10, 11}. In the past it was believed that poor cardiovascular health in adults was a long-term effect of increased body mass. However, recent studies show that even obese children are developing signs of heart disease^{12, 13}. Currently, nearly 20% of our nation’s children are obese, and the percentage is even higher among certain minority groups (as high as 50% in some groups, i.e. African Americans and Hispanics)^{2, 5, 6, 14}. If the current trends continue, 45% of children in the United States will be obese within the next 10 years⁵. Unfortunately, 80% of these obese children will remain obese as adults¹⁵. This is due in part to the persistence of early-established lifestyle habits into adulthood, but also due to physiologic changes that make it more difficult to achieve and maintain an ideal body weight^{2, 5, 6}. Early diagnosis and intervention for CVD prevention has therefore become a critical component of pediatric health.

As body mass increases, overall heart size increases due to increased cardiac workload¹⁶. In humans, morbid obesity leads to concentric hypertrophy (i.e., thickening of the walls with impingement of the chamber) and increased left ventricular mass, clearly established independent risk factors for CVD^{17, 18}. While some hypertrophy of the left ventricle may be a normal physiologic response to increased body mass, the degree of hypertrophy that is considered normal is controversial^{16, 19}. Cardiac health is compromised when hypertrophy adversely affects cardiac function (diastolic dysfunction). Lean body mass appears to have a linear relationship with cardiac size²⁰. However, the effects of fat mass are less clear. In the past 2 decades, body mass index and waist circumference measurements have been used to categorize obesity and to assess CVD risk. Recent studies have found these methods to be unreliable and suggest that CVD is more closely linked to percent fat mass^20–22. Additionally, the distribution of fat may play a role in its effect on cardiovascular risk²³. Central fat appears to have a more detrimental effect on heart health than peripheral fat²³. In monkeys, the effect of increased body fat on overall cardiac health is unknown, but obese and lean animals of the same weight would not be expected to have equivalent cardiac wall and chamber dimensions.

Cardiovascular Disease and Metabolic Syndrome

Metabolic syndrome, an increasingly common human age-related disorder driven mainly by the rising prevalence of obesity²⁴, was originally recognized in 1988 as a multiplex risk for CVD. It includes components of insulin resistance, hyperinsulinemia, glucose intolerance, increased triglycerides, decreased high-density lipoprotein (HDL) cholesterol, and hypertension²⁵. More recent definitions include obesity, or specifically abdominal obesity, in the diagnostic criteria^26–31. Although there is ongoing debate regarding the existence of and diagnostic criteria for metabolic syndrome³², it is known to be a clustering of risk factors associated with increased risk of cardiovascular morbidity and mortality. A recent meta-analysis has shown that metabolic syndrome almost doubles the risk of developing CVD, and that an excess risk for cardiovascular events and death remains even after adjusting for traditional cardiovascular risk factors in people with metabolic syndrome³³.

Debate regarding the primary etiology of metabolic syndrome centers on theories starting with either insulin resistance or obesity³⁴. It seems likely, however, that insulin resistance is a result of increasing adiposity with inflammation being the key mediating factor^{35, 36}. Systemic inflammation can cause impaired insulin action and is strongly associated with adipose tissue deposition. Adipocytes and monocyte-derived macrophages resident in the expanded adipose depot lead to increased generation of pro-inflammatory cytokines^37–39. However, it is unclear if inflammation is the cause or a consequence in metabolic syndrome. Circulating markers of systemic inflammation such as C-reactive protein (CRP), tumor necrosis factor-α, and interleukin-6 are clearly associated with metabolic syndrome^40–45, but there is also evidence that CRP levels can predict the development of metabolic syndrome in healthy people^{46, 47}. In addition, several components of the metabolic syndrome may lead to chronic low levels of inflammation. It is also possible that resistance to the anti-inflammatory actions of insulin contributes to the increased levels of inflammatory cytokines, thereby maintaining low-grade inflammation⁴². Furthermore, the increased morbidity and mortality associated with metabolic syndrome may in part be a consequence of exaggerated acute postprandial responses. For example, there is recent evidence that postprandial vascular dysfunction is more pronounced in individuals with metabolic syndrome⁴⁸.

Caloric Restriction

Caloric restriction (CR) offers a powerful way to explore the aging process, because it is the only environmental or lifestyle intervention that has repeatedly and strongly been shown to increase maximum life span and retard aging in laboratory rodents^49–52. The ability of CR to increase life span extends to fish, spiders and other animals. Dogs on CR show an increased healthy life span and average life span^{53, 54}. In most rodent CR studies, mice or rats are fed 50–70% as many calories as controls, while avoiding deficiencies in essential nutrients. The beneficial actions of CR described below depend on chronic restriction of calorie intake without malnutrition.

Currently, the majority of CR research can be divided into three general areas. First, studies are being conducted to understand the mechanism(s) by which CR is able to extend median and maximal lifespan. The vast majority of this work is being undertaken in model organisms such as Saccharomyces cerevisiae (yeast), Caenorhabditis elegans (worms), Drosophila melanogaster (fruit flies), mice, and rats. Second, there are explorations underway to determine if the positive effects of CR that have been documented in rodents extend to primates, both nonhuman and human. Finally, efforts are underway to identify or develop potential CR mimetics that would allow the positive effects of CR to be realized without the need for dietary manipulation. The remainder of this review will focus mainly on studies in nonhuman primates, specifically rhesus monkeys, and humans.

The Rhesus Monkey Model of Caloric Restriction

The rhesus monkey (Macaca mulatta), an Old World primate of either Indian or Asian origin, is a commonly used and extensively characterized biomedical model. Due to their evolutionary proximity to humans, data from this model is easily translatable to human medicine^55–58. Similarities between rhesus monkeys and humans extend to almost all aspects of anatomy, physiology, neurology, endocrinology, immunology, behaviour, and aging processes^{59, 60}. Of particular importance, rhesus monkeys develop spontaneous obesity, metabolic syndrome, and CVD^61–63. As in humans, they form advanced atherosclerotic lesions, demonstrate plaque mineralization, and are subject to complications^64–66 including myocardial infarction⁶⁵.

Two studies designed to test the long-term effects of CR in nonhuman primates are ongoing, one at the National Institute on Aging (NIA)^{67, 68} and ours at the Wisconsin National Primate Research Center (WNPRC)^{69, 70}. Both trials have shown that long-term CR can be carried out safely and is associated with indications of improved health. Additional support for the beneficial effects of CR in nonhuman primates derives from a long-term study at the University of Maryland that focuses specifically on obesity and diabetes⁷¹, and from a 4-year study in cynomolgus macaques (Macaca fascicularis) designed to evaluate the effects of CR on the development of atherosclerosis⁷². Among the many improvements in health, monkeys on long-term, moderate CR show improvements in many factors related to the metabolic syndrome, including decreased body weight and fat mass, and improved glucoregulatory function and lipid profile compared to ad libitum fed controls (Table 1).

Table 1.

Effects of Caloric Restriction on Factors of the Metabolic Syndrome in Nonhuman Primates and Humans

Measurement	Nonhuman Primates	Humans
Body weight	↓(69, 70, 73, 74, 81,99, 100)	↓(92–94)
Body fat	↓(69,73, 74, 81,99–101)	↓(92–94)
Basal glucose/insulin	↓(75–78)	↓(90–92, 95,96)
Insulin sensitivity	↑(74–78, 81)	↑(90, 91)
Blood pressure	↓(68, 82)	↓(89, 92, 102)
Triglycerides	↓(83, 85, 103)	↓(95, 98)
HDL-cholesterol	↑(84,85, 103)	↑(95, 98)

↑ Indicates an increase in the measured parameter with CR.

↓ Indicates a decrease in the measured parameter with CR.

CR: caloric restriction; HDL: high-density lipoprotein

It is not surprising that nonhuman primates on long-term CR have lower body weight when compared to ad libitum fed animals. By design, animals assigned to the CR group in the NIA and WNPRC studies receive approximately 70% of their ad libitum food allotment^{67, 69}. Correspondingly, the CR animals weigh approximately 30% less than their age- and sex-matched control counterparts. It is also not surprising that the majority of this weight difference is accounted for by a decrease in fat mass. As fat distribution is known to play a role in relative risk for CVD, it is important to note that CR animals had reductions not only in total body fat, but also in fat located specifically in the abdominal region as measured by DXA⁷³, and in the abdomen and intra-abdominal compartment as measured by computed tomogrpahy⁷⁴.

Glucoregulatory function is impaired by both advancing age and obesity. With the aging of the human population and the growing obesity epidemic, diabetes has become an international health concern. Notably, the benefits of CR on glucoregulatory function are among the most consistent findings in the nonhuman primate studies. Specifically, both short- and long-term CR potently lowers fasting insulin and improves fasting glucose and glycosylated hemoglobin measures^{70, 75–78}. Furthermore, insulin sensitivity, as measured by either the minimal model assessment or the hyperinsulinemic euglycemic clamp method, is consistently increased by CR^{70, 75–81}.

Aging and obesity are also associated with a rise in systolic blood pressure, another well-recognized risk factor for CVD. There is evidence that 3 years of CR lowers blood pressure in female rhesus monkeys⁸². With regard to lipids, both the NIA and WNPRC studies have shown that CR favorably alters lipid profiles^83–85. In particular, triglyceride levels were significantly lower in CR animals compared to controls. In addition, adult CR animals had increased levels of HDL2b, the HDL fraction associated with cardioprotection. Furthermore, CR induced compositional changes in low-density lipoprotein (LDL) cholesterol particles that reduced their participation in a potentially atherogenic interaction. LDL particles from CR animals were lower in molecular weight and were depleted in triglycerides and phospholipids. In addition, LDL binding with arterial proteoglycan was reduced.

Caloric Restriction in Humans

The efficacy of CR in nonhuman primates⁸⁶ suggests that CR might be beneficial in humans as well. Epidemiological data also suggest an inverse relationship between caloric intake and aging in humans^{51, 87, 88}. Further evidence in support of benefits from moderate CR in humans derives from an unplanned observation from the Biosphere 2 experiment. In this project, eight individuals, four men and four women, lived in a completely enclosed environment that was meant to contain all necessary supplies. Unfortunately, food supplies ran short, and the individuals in the Biosphere were effectively subjected to a 2-year period of moderate CR. As in the nonhuman primate studies, participants lost weight and fat mass, and these changes were accompanied by improvements in basal glucose, basal insulin, insulin sensitivity, and blood pressure^89–91 (Table 1).

More recently, a controlled trial in humans was initiated to study the effects of CR in healthy adults. Sponsored by the National Institute on Aging, CALERIE (Comprehensive Assessment of the Long-term Effect of Reducing Intake of Energy) is a multicenter (Washington University in St. Louis, MO, Tufts University in Boston, MA, and the Pennington Biomedical Research Center in Baton Rouge, LA) study of moderate (25%) CR in approximately 150 nonobese healthy men and women between the ages of 25 and 45 years. Data from independent Phase 1 trials performed at each site prior to the multicenter trial indicate that CR in humans results in some of the same changes described in the nonhuman primate studies and in the Biosphere 2 experiment. Specifically, CR led to decreased body weight and fat mass^92–94, decreased basal insulin and glucose levels^{92, 95, 96}, increased insulin sensitivity⁹⁷, decreased blood pressure⁹², decreased triglycerides^{92, 95, 98}, and increased HDL levels^{92, 98} (Table 1).

Because of the myriad factors that affect life span in humans, the ability of CR to extend median and maximal lifespan in humans may never be known. Nonetheless, evidence from animal models and recent human experiments suggests that CR may be able to extend the healthy period of life, regardless of its ability to ultimately extend lifespan.

Summary

Cardiovascular disease is a major public health concern in the U.S., affecting approximately one in three adults and accounting for one of every 2.8 deaths. With the aging of the population and the increasing obesity epidemic, incidence and prevalence rates of CVD will continue to increase. Caloric restriction (CR) is the only intervention shown to increase maximum lifespan and retard aging in laboratory rodents and nonhuman primates. There is also strong evidence that CR improves several components of the metabolic syndrome in nonhuman primates, thereby reducing the risk of CVD and related complications. Recent data from human studies indicate that CR is likely to have similar positive effects in humans.