Guest guest Posted October 30, 2004 Report Share Posted October 30, 2004 Hi All, Rhesus monkeys' CR studies are described in the below, which are from two of three rhesus monkey cohorts' studies. The full-tests were available. In the below, only the abstract not previously posted for its Medline citation number is presented in the below. For definition of monkey, including rhesus monkey, see: monkey 1. <zoology> In the most general sense, any one of the Quadrumana, including apes, baboons, and lemurs. Any species of Quadrumana, except the lemurs. Any one of numerous species of Quadrumana (especially. Such as have a long tail and prehensile feet) exclusive of apes and baboons. The monkeys are often divided into three groups: (a) Catarrhines, or Simidae. These have an oblong head, with the oblique flat nostrils near together. Some have no tail, as the apes. All these are natives of the Old World. ( Platyrhines, or Cebidae. These have a round head, with a broad nasal septum, so that the nostrils are wide apart and directed downward. The tail is often prehensile, and the thumb is short and not opposable. These are natives of the new World. © Strepsorhines, or Lemuroidea. These have a pointed head with curved nostrils. They are natives of Southern Asia, Africa, and Madagascar. Chimpanzees are an ape -- 1. <zoology> A quadrumanous mammal, especially. Of the family Simiadae, having teeth of the same number and form as in man, having teeth of the same number and form as in man, and possessing neither a tail nor cheek pouches. The name is applied esp. To species of the genus Hylobates, and is sometimes used as a general term for all Quadrumana. The higher forms, the gorilla, chimpanzee, and ourang, are often called anthropoid apes or man apes. Chimpanzees are more closely related in terms of our genes, but the characteristics of the rhesus monkeys' behavior and pathology certainly do resemble those of humans. What about on CR? A good question in my mind, this is, and true it is for their behavior, anyway. The pathologies seem quite similar. The below seemed too important to not post. I need to apologize for he length of the text below. For comparison the Albatross has a size of 50 pages. This post is 26 pages. It is in my opinion better written also. But maybe the implications of the Albatross for those with much perseverance may be greater. I take some satisfaction in letting papers do the talking, and these two to me gems attest to the implications of CR animal studies to the human condition better than many. It is one step down for me to the value of human CR studies, for which we would be required to wait too long. In my presentation of the below, I hope that the many things that required personal attention, such as +/-'s and ='s have not overlooked many others such difficulties. Bodkin NL, TM, Ortmeyer HK, E, Hansen BC. Mortality and morbidity in laboratory-maintained Rhesus monkeys and effects of long-term dietary restriction. J Gerontol A Biol Sci Med Sci. 2003 Mar;58(3):212-9. PMID: 12634286 [PubMed - indexed for MEDLINE] THE morbidity and mortality rates for many human diseases increases with age, leading investigators to examine the effects of aging on the onset and severity of human disease. However, successful gerontological inter-vention in age-related diseases has been complicated by the variation in the rate of aging processes across individuals as well as the variation in interaction of disease pathology with the aging process across individuals (1). The rhesus monkey (Macaca mulatta) is an excellent model for the study of human aging, as it exhibits extra-ordinary similarity to humans. Behavioral and biomedical data have been documented on the rhesus monkey over at least the last eight decades, further increasing its value for the study of human aging. However, in comparing the rhesus monkey model to studies of aging in humans, additional data on morbidity and causes of death, life expectancy, life span, survival information, and related characteristics of the rhesus is needed. Previous studies from various primate centers and colonies (2–5) have provided some of these data. For exam-ple, (2) summarized mortality, fertility, and growth rates for approximately 450 captive rhesus monkeys com-pared with free-ranging (Cayo Santiago) primates and showed improved mortality and fertility in the captive mon-keys. Gage and Dyke (4) examined the mortality statistics for 25 populations of the larger Old World monkeys (Cer-copithecinae) with data analyzed for eight data sets and noted the importance of variation in environmental factors in comparing the mortality patterns in both wild and cap-tive Old World primates. Tigges and colleagues (5) studied three groups of captive rhesus monkeys at the Yerkes Regional Primate Research Center: wild-born, singly housed; wild or captive-born and socially housed; and captive-born and singly housed; mortality rates and maximum life span data were examined. Ha and colleagues (6) carried out a demographic analysis of the Washington Regional Primate Research Center Pig-tailed macaque colony over nearly 30 years and examined growth, fertility, mortality, and survival. Rawlins and co-workers (7) summarized the demographic, reproductive, and anthropometric data from 1976 to 1983 on the free-ranging rhesus primate colony of Cayo Santiago, Puerto Rico. Therefore, the current study is provided to further this primate information base, focusing on morbidity and mor-tality in laboratory-held rhesus monkeys. In addition, the lay population, clinicians, and gerontologists, in particular, have recently focused on which therapies or interven-tions might be used to achieve not only a longer life, but an increased quality of life. Clearly, in several rodent species studied over the last 60 years, dietary restriction (generally referred to as a 30–40% decrease in caloric intake without malnutrition) has shown reproducible effects to prolong life span (8–10). There are currently three groups studying dietary re-striction in nonhuman primates: the National Institute on Aging (NIA), which began in 1987 (11,12), the University of Wisconsin at Madison (UW), which began in 1991 (13– 15), and the current study at the University of -land Obesity, Diabetes and Aging Animal Resource Center (ODAAR), Baltimore (16–20). In addition, a shorter term (5-year) study of calorie restriction in nonhuman primates was conducted at Bowman Gray University (21). Each of the groups has now compiled data addressing multiple effects of dietary restriction in nonhuman primates. Among these multiple physiological effects, dietary re-striction leads to the prevention of obesity (16,19), decreased plasma insulin levels (12,13,15,16,21,22), increased insulin sensitivity (12,13,15,17), and decreased atherosclerosis (21,23), relative to ad libitum (AL)-fed primates. However, to date, there have been limited data regarding the effects of dietary restriction on mortality and morbidity. The purpose of this study is to determine if there were differences in the survival (mortality) and morbidity (causes of death) of two groups of rhesus monkeys from the Obesity and Diabetes Research Center (ODRC) at the University of land, Baltimore. The two groups of monkeys were defined based on their dietary regimen, which differed only in the amount of diet provided. The first group, referred to as the AL monkeys, was provided standard well-balanced pri-mate chow, which was always available; that is, the amount consumed was not restricted. The second group, referred to as the dietary-restricted (DR) monkeys, was provided the identical well-balanced primate chow; however, the chow was provided in amounts adjusted to maintain a healthy adult body weight in a predetermined range (details of both feeding regimens are described below). All the monkeys were metabolically well characterized and maintained under constant dietary and environmental conditions. The variables included were age, weight, fasting plasma insulin (IRI), fasting plasma glucose (FPG), glucose tolerance (glucose disappearance rate during an intravenous glucose tolerance test), acute insulin response during an intravenous glucose tolerance test (AIR), and insulin sensi-tivity (M; estimated during a euglycemic, hyperinsulinemic clamp). We sought to determine if there were differences in the survival of the two groups of monkeys based on AL versus DR conditions, and to identify the major morbidity and causes of death in each group, including associations with metabolic factors. METHODS Subjects One hundred seventeen rhesus monkeys (Macaca mu-latta) were studied (21 females and 96 males). One hundred nine of the monkeys (88 males and 21 females) were AL fed and 8 monkeys (all male) were DR (details of the protocol described below). All monkeys were part of a longitudinal study of aging, obesity, and spontaneous type 2 diabetes mellitus and were individually housed. Data were obtained from approximately January 1977 to July 1, 2001, a period of almost 25 years. The selection criteria for the subjects are described below. During the course of study, 52 mon-keys died (49 of the AL-fed monkeys and 3 of the DR monkeys). These deaths were due to natural causes as de-tailed below. All monkeys were maintained on monkey chow (Purina Mills, St. Louis, MO), composed of 70% carbohydrate, 17% protein, and 13% fat. In the case of 16 of the AL-fed monkeys, a nutritionally complete liquid diet, Ensure (Ross Laboratories, Columbus, OH), was occasionally used. For all monkeys, the diet conditions described below were initiated as soon as the monkeys were released from quarantine. The AL-fed monkeys were provided the diet in an amount that allowed for food to be readily available 24 hours/day and which allowed each monkey to determine its daily intake on an individual basis. Therefore, in the AL monkeys, food intake per monkey was entirely individually determined. The DR monkeys were maintained on monkey chow (Purina Mills), which was calorically titrated on an individual monkey basis to maintain a goal weight of 10 to 11 kg, the weight of normal lean adult monkeys (19). This body weight is associated with a body fat ranging from approximately 17–24% (16,19,24). Each monkey was weighed a minimum of once weekly, and the individual daily chow allotment was adjusted up or down for each monkey depending on any change in its body weight. This caloric titration usually required an increase or decrease of one to two biscuits per day. The DR monkeys were fed in three equal amounts at approximately 8 AM,1PM, and 4 PM. For both AL and DR monkeys, the primate husbandry in the ODRC was meticulously carried out, including counting of biscuits eaten per day in all monkeys and direct and discrete observation of all monkeys throughout the day. In addition, the monkeys were weighed weekly and all mon-keys received a daily chewable multiple vitamin and fresh water ad libitum. Selection Criteria and Methods The monkeys in this study were obtained from the fol-lowing sources: primate center breeding colonies (n = 41), commercial breeding colonies (n = 32), research laborato-ries (n = 42), and miscellaneous sources (n = 2). All monkeys were maintained on monkey chow prior to purchase and were research naý¨ve. The prenatal conditions of the monkeys were not quantified or recorded. Prior to purchase, each primate was screened by the clin-ical veterinarian for adequate health status and normal health parameters. This process included background information from the attending veterinarian at the originating facility and the medical record of the monkey. All monkeys were required to have a negative tuberculosis test, undergo a standard physical exam, have a normal chemistry/hematol-ogy profile (indicating normal electrolyte, liver, and kidney function), be research naý¨ve, and have normal laboratory behavioral characteristics. Monkeys were included in the study based on the fol-lowing criteria: All monkeys had a recorded age and a known laboratory and medical history prior to acquisition into the colony. Fifty of the 52 monkeys that died were humanely euthanized due to a veterinary diagnosis indicating that death was imminent, including a diagnosis of a terminal condition or significant morbidity not amenable to treatment. Eutha-nasia was carried out using 100 mg/kg pentobarbital administered intravenously. Two of the 52 monkeys were found in the morning to have expired during the night. In all cases the necropsy was carried out immediately. Data Analysis Basic descriptive statistics regarding the two groups of monkeys were calculated. A proportional hazards regression model was used to estimate the difference in the mortality rate for the two dietary groups: AL versus DR monkeys. This model assumes that the hazard rates (i.e., the risk of death at a given age) for the two groups are proportional to each other. The survival times were left truncated; therefore, a monkey contributed to the survival estimate beginning at the age at which it entered the laboratory, the time that all monkeys were known to exist under the same environmental conditions. In addition, the model was tested for a possible effect of the source of acquisition on survival. Secondary analyses compared a) the mortality rate for the DR monkeys with the AL-fed monkeys, and the AL-fed monkeys classified as follows: normal (fasting plasma glu-cose <126 mg/dl and fasting plasma insulin <70 lU/ml), hyperinsulinemic (fasting plasma glucose <126 mg/dl and fasting plasma insulin .70 lU/ml), or diabetic (fasting plasma glucose .126 mg/dl), and the mortality rate for the two groups of monkeys stratified by diet treatment (AL fed vs DR) after adjusting for the baseline metabolic char- acteristics: body weight, fasting plasma glucose, fasting plasma insulin, and peripheral insulin sensitivity. The age at death, the major cause of death, and organ pathology present at death were determined for each mon-key based on the individual necropsy reports. Associations between the causes of death and the age at death with gender and diabetic status of the monkeys were tested using two-sample t-tests and Fisher's exact test. RESULTS Table 1 presents the baseline characteristics of the mon-keys in each dietary group. Table 1. Summary Characteristics of the Monkeys Variable/Group Mean SD N Range Age at entry (y) Dietary restricted 16.6 2.1 8 12–19 Ad libitum fed (normal) 12.6 5.7 64 4–28 Ad libitum fed (hyperinsulinemic) 12.8 5.4 22 7–26 Ad libitum fed (diabetic) 20.8 4.9 20 13–29 Age at death/censoring (y) Dietary restricted 26.9 3.6 8 21–30 Ad libitum fed (normal) 20.6 7.2 64 9–34 Ad libitum fed (hyperinsulinemic) 18.6 6.3 22 10–35 Ad libitum fed (diabetic) 25.5 6.0 20 16–40 Body weight (kg) Dietary restricted 10.3 0.8 8 9.5–11.6 Ad libitum fed (normal) 11.8 3.7 64 4.8–24.7 Ad libitum fed (hyperinsulinemic) 13.4 3.6 20 4.8–17.8 Ad libitum fed (diabetic) 9.5 4.5 20 4.5–22.2 Fasting plasma glucose (mg/dl) Dietary restricted 60 5 8 52–67 Ad libitum fed (normal) 64 8 62 47–92 Ad libitum fed (hyperinsulinemic) 67 +/- 22 50–77 Ad libitum fed (diabetic) 196 79 20 129–384 Fasting plasma insulin (lU/ml) Dietary restricted 14 +/- 8 5–23 Ad libitum fed (normal) 42 15 61 11–67 Ad libitum fed (hyperinsulinemic) 105 85 22 40–446 Ad libitum fed (diabetic) 63 82 19 3–239 Glucose disappearance rate (%/min) Dietary restricted 3.9 0.96 8 2.6–5.7 Ad libitum fed (normal) 3.6 0.90 51 2.0–5.5 Ad libitum fed (hyperinsulinemic) 3.1 0.85 18 2.1–5.1 Ad libitum fed (diabetic) 1.2 0.40 18 0.7–2.3 Acute insulin response (lU/ml/min) Dietary restricted 106 60 8 44–228 Ad libitum fed (normal) 131 89 45 27–470 Ad libitum fed (hyperinsulinemic) 378 388 15 73–1635 Ad libitum fed (diabetic) 27 54 15 1–160 Peripheral insulin sensitivity (mg/kg FFM/min) Dietary restricted 14.1 6.3 7 6.6–23.9 Ad libitum fed (normal) 12.3 3.7 48 4.6–19.5 Ad libitum fed (hyperinsulinemic) 7.6 3.3 16 1.6–13.9 Ad libitum fed (diabetic) 7.3 2.4 7 4.2–10.1 Note: All but ``Age at death " were data collected on entry to the study. The AL-fed monkeys have been subgrouped as AL normal, AL hyperinsulinemic, and AL diabetic. The baseline metabolic characteristics of these AL monkeys (which ranged from young normal to obese hy-perinsulinemic to type 2 diabetes) were as follows: Fasting plasma glucose concentrations ranged from 47–384 mg/dl and fasting plasma insulin concentrations ranged from 3–446 lU/ml. Glucose disappearance rate during an intravenous glucose tolerance test ranged from 0.68–5.70 %/min and acute insulin response (baseline to 10 minutes) to intrave-nous glucose ranged from 1–1636 lU/ml/min. Peripheral in-sulin sensitivity (M) ranged from 1.63–23.92 mg/kg FFM/ min. Type 2 diabetes was defined as two or more observa-tions of fasting plasma glucose concentration =/> 126 mg/dl, consistent with the diagnostic criteria of the American Diabetes Association (25). We found no statistically significant differences between the risk of death comparing the DR monkeys with the AL monkeys ( p 5 .1), although we estimated that the free-feeding condition compared with DR feeding led to approximately 2.6-fold higher risk of death in the AL monkeys (95% Confidence Interval [CI]: 0.82—8.70). These results were not sensitive to adjustment for the source of acquisition (hazard ratio : 2.6; 95% CI: 0.77–8.85). Similar results were found when restricting the analysis to those monkeys that entered the study from 12 to 18 years of age (age range for DR monkeys): the estimated HR is 2.27 (95% CI: 0.65– 7.94). Estimated median survival based on analysis of the AL-fed monkeys versus the DR monkeys was approximately 25 and 32 years for the AL and DR monkeys, respectively. We also compared the risk of mortality for three metabolic classifications of the AL-fed monkeys (normal, hyperinsulinemic, and diabetic) to the risk of mortality for the DR monkeys). Table 2 presents the estimated HRs and corresponding 95% CIs. Table 2. Estimated Hazard Ratios and 95% Confidence Intervals Comparing Four Classifications of Monkeys: Dietary-restricted, Ad Libitum Fed Normal, Ad Libitum Hyperinsulinemic, and Ad Libitum Diabetic Groups Reference group Comparison Group N Hazard Ratio (95% Confidence Interval) Dietary restricted AL Normal 58 2.56 (.76–8.57) AL Hyperinsulinemic 33 3.71 (1.02–13.62) AL Diabetic 18 2.37 (.65–8.68) AL Normal Dietary restricted 8 0.42 (.13–1.39) AL Hyperinsulinemic 33 1.58 (.79–3.15) AL Diabetic 18 2.65 (.78–9.04) Note:AL ad libitum. The risk of death for a hyper-insulinemic monkey was 3.7 times higher than the risk of death for a DR monkey of the same age (95% CI: 1.02– 13.62; p ,.05). Figure 1 presents the estimated survival curves for the DR monkeys versus the normal, hyper-insulinemic, and diabetic groups of monkeys, with the age at median survival indicated for each metabolic group. When restricting the analysis to compare mortality for only AL normal monkeys and DR monkeys, the estimated HR is 2.33 (95% CI: 0.68–7.94). Table 3 presents the estimated HRs and 95% CI com-paring AL-fed versus DR monkeys after adjusting for body Table 3. Estimated Hazard Ratios and 95% Confidence Interval in the Two Dietary Groups After adjusting for Metabolic Characteristics Group/Characteristic Hazard Ratio 95% Confidence Interval Dietary restricted 1.00 — Ad libitum fed 4.63 .86–25.00 Body weight (kg) .76 .63–.91 Fasting plasma insulin (lU/ml) 1.03 1.00–1.06 Fasting plasma glucose (mg/dl) 1.07 .91–1.26 Insulin sensitivity (M) (mg/kg FFM/min) .93 .80–1.07 Note: The hazard ratio for plasma glucose and insulin is shown per 10 unit change in these variables. weight, fasting plasma insulin, fasting plasma glucose, and peripheral insulin sensitivity (M). Results showed that the risk of death for an AL-fed monkey decreases by 7% per unit increase in insulin sensitivity (M) with a 95% CI of 0.80–1.07, although this value was not statistically significant. In the course of the study, three of the DR monkeys died, and the oldest of these DR monkeys (age 30 years at death) had significant pathology present (case findings discussed further in Discussion). There were no significant differences between the average age at death of males to females ( p 5 ..7) and diabetics to nondiabetics ( p 5 .8), and there were no differences in gender or diabetic status related to significant pathology at death. Table 4 summarizes the proximal cause of death by organ system. Table 4. Proximal (Major) Cause of Death by Organ System in All Monkeys Organ System Monkeys (N) Age at Death (y) (Mean +/- SD) Proportion With Diabetes (at Death) Cardiac 11 25 +/- 8 7/11 (64%) Respiratory 3 25 +/- 5 3/3 (100%) Cardio/respiratory 4 30 +/- 5 1/4 (25%) Gastrointestinal 6 21 +/- 8 0/6 (0%) Hepatic 4 26 +/- 5 2/4 (50%) Renal 6 22 +/- 6 4/6 (67%) Reproductive 4 21 +/- 5 3/4 (75%) Cerebrovascular 3 27 +/- 4 3/3 (100%) Musculoskeletal 2 28 +/- 2 2/2 (100%) TOTAL 43* 25 +/- 6 25/43 (58%) Note: * Nine monkeys had multiple severe pathology, where the proximal cause of death was not determined. The major (proximal) cause of death in this group of monkeys was cardiac related and included such pathology as endocarditis, aortic valve calcification, fibrosis, cardiac hypertrophy, myocardial infarction, acute cardiac arrest, and congestive heart failure. The next most-prevalent organ sys-tems leading to death involved the gastrointestinal system and the kidney. Interestingly, based on age at death, the monkeys dying of gastrointestinal disease (mean +/- SD: 21 +/- 8 years of age at death) or renal disease (mean +/- SD: 22 +/- 6 years of age at death) were several years younger on average than the monkeys dying of cardiac-related disease (average age 25 +/- 8 years) or hepatic-related disease (26 6 5 years). The presence of type 2 diabetes mellitus in the mon-keys was clearly a pathological factor, as the proportion of diabetic to nondiabetic monkeys in all categories (cardiac, respiratory, hepatic, renal, reproductive, and cerebrovascular) ranged from 25–100% by group. Only the gastrointestinal category (as the major cause of death) was without diabetic monkeys. Table 5 summarizes the organ pathology identified at death by dietary treatment group. Table 5. Incidence of Moderate and Severe Pathology in the Five Major Organ Systems in All Monkeys (Identified by Dietary Treatment Group) at Death Organ System Ad Libitum Fed Dietary Restricted Cardiovascular Severe 21 1 Moderate 0 0 Respiratory Severe 20 1 Moderate 12 1 Gastrointestinal Severe 20 2 Moderate 2 0 Hepatic Severe 16 1 Moderate 2 0 Renal Severe 6 0 Moderate 8 1 Note: Due to multiple pathology, particularly in the ad libitum- fed pri-mates, monkeys may be represented in a disease category more than once. Considering severe and moderate pathology, the most prevalent organ pathology in all monkeys involved the respiratory system. In the AL-fed monkeys, the most frequent respiratory-related complica-tions included: lung mites (Pneumonyssus simicola, ranging from mild to severe), pneumonia, and bronchiolitis. Other pathologic respiratory complications included emphysemic changes, pulmonary edema, pulmonary artery thrombosis, and pleural adhesions. Additional significant pathology was present in the gastrointestinal system (bowel obstruction, diverticulitis, and gastritis), cardiac (as noted previously), renal (glomerulosclerosis and glomerulonephritis), and liver (fatty infiltration, amyloidosis, hepatitis, and hepatic degen- eration). The organ pathology of the three DR monkeys that died will be detailed in the Discussion. DISCUSSION The purpose of this study was to describe mortality in a well-established, metabolically well-characterized colony of laboratory-maintained rhesus monkeys. In addition, we examined the effects of long-term dietary restriction, if any, on these same parameters. Specifically, we addressed the questions of whether DR monkeys had improved quality of life, improved health status, and/or extension of the life span compared with the AL-fed, control monkeys. Results showed the risk of death for an AL fed monkey was 2.6-fold higher than the risk of death for a DR mon-key of the same age. Recognizing the limitations of the sam-ple size in the DR group, we estimate that the power to significantly detect a 2.6-fold increase in risk of death in the AL monkeys compared with the DR monkeys is ap-proximately 0.15. Although our study has low power to significantly detect a difference in the risk of death, the study does provide preliminary data that the calorie restriction regimen will improve survival in laboratory-held primates, as compared with AL feeding. The median survival age in the AL-fed monkeys was 25 years of age. In contrast, the surviving DR monkeys as of July 1, 2001, have attained an average age of 30 +/- 2 years. What the cause(s) of death will be in the surviving DR monkeys is not yet known, and whether there will be a significant difference in the average age at death compared with the AL monkeys awaits further study. Eight and one-half years after initiation of dietary re-striction in the University of Wisconsin primate study, both the DR and control monkeys are in good health (15). Two deaths in each group (originally 15 monkeys each) have been noted: 1 control monkey death was due to herniation of the colon, and 1 DR monkey death was due to asymptomatic cardiomyopathy; in addition, 1 death in each group was anesthesia related (15). Support for increased longevity from dietary restriction feeding in primates compared with controls has been reported by a National Institute on Aging group showing trends consistent with decreased mortality Figure 1. Estimated survival curves comparing the dietary-restricted monkeys (26). This decreased mortality is due to a lower incidence of chronic disease, including cardiovascular disease, neoplasm, diabetes, endometriosis, and kidney failure in the DR versus AL-fed primates (27). Our present findings are consistent with these important studies. The data were also examined in regard to the effect of different metabolic characteristics of the monkeys on survival. The risk of death for a hyperinsulinemic monkey was 3.7 times higher ( p ,.05) as compared with a DR monkey of the same age. Hyperinsulinemia has been implicated in the pathogenesis of a number of disorders, including obesity, glucose intolerance, and type 2 diabetes in primates (28–30) and dyslipidemia (31). Weyer and colleagues (32) studied 319 nondiabetic Pima Indians with normal glucose tolerance prospectively and found that fasting hyperinsulinemia has a primary role in the pathogenesis of type 2 diabetes, independent of insulin resistance. Additionally, Gwinup and Elias (33) have proposed systemic hyperinsulinemia as a major factor in the development of atherosclerosis, micro- angiopathy, nephropathy, and type 2 diabetes mellitus, a hypothesis consistent with the present findings. Comparison of the AL-fed monkeys and the DR monkeys, after adjusting for baseline body weight, fasting plasma insulin, fasting plasma glucose, and peripheral insulin sensitivity (M), showed that the risk of death was decreased by 7% per unit increase in insulin sensitivity. There is good evidence in primates (34,35) and in humans (36,37) to support a close relationship between fasting plasma insulin and insulin sensitivity. Increased survival associated with improved insulin sensitivity is therefore consistent with the previous finding of increased survival and normoinsulinemia. In addition, decreased peripheral insulin sensitivity (in-sulin resistance), such as hyperinsulinemia, is a risk factor in the development of obesity, glucose intolerance, dys-lipidemia, type 2 diabetes mellitus, hypertension, and the metabolic syndrome in both primates (31) and humans (38–40). Increased mortality is also associated with these disorders. Dietary restriction has been shown to lead to improved glucose utilization in rodents (41) and in primates (12,14,15,17,21,42). Therefore, our data show preliminary evidence that the improved glucoregulation and insulin sensitivity associated with dietary restriction may be a factor underlying protection against age-related disease, decreased morbidity, and increased survival in primates. Regarding major causes of death, in this study there were no significant differences between male and female monkeys and between nondiabetics and diabetics in regard to age at death. These findings are similar to those of Sievers and coworkers (43) who studied diabetic and nondiabetic Pima Indians and found that overall cause-specific death rates, when age- and sex-adjusted, were not significantly different between nondiabetic and diabetic subjects. Regarding cardiac-related morbidity, the 11 monkeys that exhibited cardiac pathology as the (proximal) major cause of death had an average age at death of 25 +/- 8 years. None of the DR monkeys had cardiac pathology at death, although the three DR monkeys that died were 21, 23, and 30 years of age at death (average age, 25 +/- 5 years). These findings lend additional support to the importance of dietary restriction in maintaining normal plasma insulin levels and insulin sensitivity, and therefore, imparting metabolic protection to these monkeys regarding cardiac disease, atherosclerosis, and related pathology. Studies of type 2 diabetes mellitus in humans have shown that although hyperglycemia and hypertension contribute to the mortality of type 2 diabetes, atherosclerosis is the major cause of death. Ford and Stefano (44) found that approximately 50% of mortality in diabetic humans is related to coronary disease. Standl (45) estimated that coronary heart disease and stroke may account for greater than 75% of deaths in patients with type 2 diabetes. Three of the eight DR monkeys died during the course of the study. In this limited sample to date, the organ pa-thology at death in these primates under the DR regimen was as follows. The first monkey died of acute gastroin-testinal bloat at 21 years of age. At necropsy, the stomach was markedly dilated, filling almost the entire abdomen. Although there was no food in the stomach, there was approximately 20 ml of fluid in the intestinal tract, and no intestinal blockage or specific intestinal pathology was found. There were no significant lesions in the brain, kidney, liver, or spleen. Bronchiolitis, lung congestion, and pneumonia were also noted, associated with lung mite infestation. The condition of bloat in primates, known as gastric dilatation, was described in 1967 (46). Findings have included rupture of the stomach wall, bowel distension, and abdominal hernia (47), and this disorder has been de-scribed as one of sporadic occurrence with high mortality in apparently healthy monkeys (48). Etiology has been attributed to infection, anesthesia, changes in routine, and excessive eating and drinking (47); our current monkey had received ketamine for an experiment the day prior to the morning when he was found dead. The second DR monkey, which died at age 23 years, was diagnosed with systemic lupus erythematosus (SLE). In humans, this chronic inflammatory disease of connective tissue is classified as an autoimmune disorder that affects the skin, joints, kidneys, nervous system, and mucous membranes. In this primate, the clinical situation presented as inappetance, anemia, leukopenia, decreased activity, gener-alized muscular atrophy evident in the limbs, and decreased range of motion, particularly in the rear limbs. Radiographs revealed severe discospondylosis in the thoracic, lumbar, sacral, and tail vertebrae as well as marked intravertebral bridging and narrowing of the disc spaces. A viral screen for herpes B virus, herpes simplex virus-1, measles, simian retrovirus, and simian immunodeficiency virus was negative. Additional diagnostic work-up showed an antinuclear antibody titer of 1:160 (reference values of a positive titer in young canines as .1:20 and in older canines as 1:60) and clinical signs that included proteinuria, anemia, and leukopenia. A clinical diagnosis of SLE was made. Spontaneous SLE has been rarely documented in macaques; an earlier case in an adult male rhesus (age not stated) was described by and Klein (49) with a clinical course similar to the present case. Diet-induced SLE in adult female cynomolgus macaques was produced by the feeding of alfalfa seeds (50,51). It has been noted (10) that dietary restriction has been shown to prevent the development of autoimmune disease in susceptible mice strains, including a lupus-like nephropathy. This response may be species specific, as a primate report (52) measuring the peripheral blood mononuclear cell response to various mitogens was decreased in DR rhesus monkeys versus control monkeys, indicating that perhaps the primate immunological response was not improved by dietary restriction. The third DR monkey died at age 30 with major gas-trointestinal pathology as the proximal cause of death, specifically, colonic adenocarcinoma with metastases to the liver and mesentery. It is noteworthy that this DR monkey lived approximately 9 years longer than the average age of death of the AL-fed monkeys with gastrointestinal disease as the major cause of death. Among the AL-fed monkeys, median survival was ap-proximately 25 years of age. We would propose, therefore, that this biological threshold is a good indication of an ``aged " rhesus monkey. At or after 25 years of age, and certainly by age 30 years and older, the rhesus monkey appears to reflect the characteristic senescent changes of the elderly human population. Currently, there are 15 monkeys in the ODRC colony that are older than 25 years; in this group there are 5 DR monkeys (average age 30 +/- 2 years); next in age are 3 diabetic monkeys (average age 29 +/- .5 years) and 1 old normal monkey (age 28.1 years), and 7 aged monkeys between 25 and 28 years of age. At this point, as the average age of the DR monkeys is about 7 primate years older than the median survival age in the AL-fed mon-keys (25 years of age), we might speculate that dietary re-striction, if applied to humans, might lead to an extension of median survival. Although it is not yet known whether maximal life span will be extended by dietary restriction in primates, data relevant to AL feeding and longevity have resulted from the current study. Previously, Tigges and colleagues (5) documented the oldest known rhesus monkey (male), maintained at the Yerkes Regional Primate Research Center, Emory University. This monkey was 35 years old when he died, significantly older than the median survival age found in the present analysis. In the current study the oldest male rhesus (Monkey M-5) also lived to be 35 years old; in spite of life-long AL feeding and a history of obesity, he re-mained nondiabetic throughout life. His major pathology at time of death included cardiorespiratory pathology (enlarged heart with thickening of the heart valves and multifocal diffuse emphysemic changes in the lungs). The oldest primate in the current study (Monkey L-9; a female rhesus), which was also maintained on ad libitum feeding, lived to the remarkable age of 40 years old. She had been diagnosed with type 2 diabetes mellitus at age 29 years and, therefore, was maintained on insulin therapy for ap-proximately 11 years. Although this centenarian primate was diabetic, on insulin therapy, and had limited vision, she was otherwise in excellent health, physically active, and alert even at her advanced age. Approximately 6 hours before her death, her level of consciousness decreased, her color became dusky, and she began to deteriorate rapidly. Elective euthanasia was necessary. At necropsy, the proximal cause of death was cardiac related: endocarditis of the tricuspid valve and previous myocardial infarction. To our knowl-edge, she is the oldest rhesus monkey documented and provides evidence that the maximal life span of the rhesus monkey in the laboratory setting is 40 years of age. Our findings in the rhesus monkey supplement the ex-isting database from several other species, providing pre- liminary data that the health-producing effects of dietary restriction led to an increase in average age of survival. In addition, our results suggest that dietary restriction decreased age-related morbidity in the nonhuman primate, associated with the prevention of hyperinsulinemia and the mitigation of several major age-related diseases. REFERENCES 1. Horiuchi S, Wilmoth JR. Age patterns of the life table aging rate for major causes of death in Japan, 1951–1990. J Gerontol Biol Sci. 1997; 52A:B67–B77. 2. D. A comparison of the demographic structure and growth of free-ranging and captive groups of rhesus monkeys (Macaca mulatta). Primates. 1982;23:24–30. 3. Dyke B, Gage T, Mamelka P, Goy R, Stone W. A demographic analysis of the Wisconsin Regional Primate Center Rhesus Colony, 1962–1982. Am J Primatol. 1986;10:257–269. 4. Gage T, Dyke B. Model life tables for the larger old world monkeys. Am J Primatol. 1988;16:305–320. 5. Tigges J, Gordon T, McClure H, Hall E, s A. Survival rate and life span of rhesus monkeys at the Yerkes Regional Primate Research Center. Am J Primatol. 1988;15:263–273. 6. Ha JC, Robinette RL, Sackett GP. Demographic analysis of the Washington Regional Primate Research Center pigtailed macaque colony, 1967–1996. Am J Primatol. 2000;52:187–198. 7. Rawlins RG, Kessler MJ, Turnquist JE. Reproductive performance, population dynamics and anthropometrics of the free-ranging Cayo Santiago rhesus macaques. J Med Primatol. 1984;13:247–259. 8. McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. J Nutr. 1935;10:63–79. 9. Weindruch R, Walford RL. The Retardation of Aging and Disease by Dietary Restriction. Springfield, IL: C. ; 1988. 10. Weindruch R, Sohal RS. Review article. Caloric intake and aging. N Engl J Med. 1997;337:986–994. 11. Ingram DK, Cutler RG, Weindruch R, et al. Dietary restriction and aging: the initiation of a primate study. J Gerontol Biol Sci. 1990;45: B148–B163. 12. Lane M, Ball S, Ingram D, et al. Diet restriction in rhesus monkeys lowers fasting and glucose-stimulated glucoregulatory endpoints. Am J Physiol Endocrinol Metab. 1995;268:E941–E948. 13. Kemnitz JW, Weindruch R, Roecker EB, Crawford K, Kaufman PL, Ershler WB. Dietary restriction of adult male rhesus monkeys: design, methodology, and preliminary findings from the first year of study. J Gerontol Biol Sci. 1993;48:B17–B26. 14. Kemnitz JW, Roecker EB, Weindruch R, Elson DF, Baum ST, Bergman RT. Dietary restriction increases insulin sensitivity and lowers blood glucose in rhesus monkeys. Am J Physiol. 1994;266:E540–E547. 15. Gresl T, Colman R, Roecker E, et al. Dietary restriction and glucose regulation in aging rhesus monkeys: a follow-up report at 8.5 yr. Am J Physiol Endocrinol Metab. 2001;281:E757–E765. 16. Hansen BC, Bodkin NL. Primary prevention of diabetes mellitus by prevention of obesity in monkeys. Diabetes. 1993;42:1809–1814. 17. Bodkin NL, Ortmeyer HK, Hansen BC. Long-term dietary restriction in older-aged rhesus monkeys: effects on insulin resistance. J Gerontol Biol Sci. 1995;50:B142–B147. 18. Ortmeyer HK, Bodkin NL, Hansen BC. Chronic caloric restriction alters glycogen metabolism in rhesus monkeys. Obes Res. 1994;2: 549–555. 19. Hansen BC, Ortmeyer HK, Bodkin NL. Prevention of obesity in middle-aged monkeys: food intake during body weight clamp. Obes Res. 1995; 3:199S–204S. 20. Hansen BC, Ortmeyer HK, Bodkin NL. Calorie restriction in non human primates: mechanisms of reduced morbidity and mortality. Toxicol Sci. In press. 21. Cefalu WT, Wagner JD, Wang ZQ, et al. A study of caloric restriction and cardiovascular aging in cynomolgus monkeys (Macaca fascicu-laris): a potential model for aging research. J Gerontol Biol Sci. 1997; 52:B10–B19. 22. Cutler RG, BJ, Ingram DK, Roth GS. Plasma concentrations of glucose, insulin, and percent glycosylated hemoglobin are unaltered by food restriction in rhesus and squirrel monkeys. J Gerontol Biol Sci. 1992;47:B9–B12. 23. Verdery RB, Ingram DK, Roth GS, Lane MA. Caloric restriction in- creases HDL2 levels in rhesus monkeys (Macca mulatta). Am J Physiol Endo. 1997;273:E714–E719. 24. Hansen BC, Bodkin NL. Heterogeneity of insulin responses: phases in the continuum leading to non-insulin-dependent diabetes mellitus. Diabetologia. 1986;29:713–719. 25. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 1997; 20:1183–1187. 26. Roth G, Ingram D, Lane M. Calorie restriction in primates: will it work and how will we know? J Am Geriatr Soc. 1999;47:896–903. 27. Mattison J, Ingram D, Roth G, Lane M. Nutritional Modulation of Aging by Caloric Restriction. Basel: Karger; 2002. 28. Metzger BL, Hansen BC, Speegle LM, Jen K-LC. Characterization of glucose intolerance in obese monkeys. J Obes Weight Reg. 1985;4: 153–167. 29. Jen K-LC, Hansen BC, Metzger BL. Adiposity, anthropometric mea- sures, and plasma insulin levels of rhesus monkeys. Int J Obes. 1985;9: 213–224. 30. Hansen BC, Bodkin NL. Beta cell hyperresponsiveness to glucose precedes both fasting hyperinsulinemia and reduced glucose tolerance [Abstract]. Diabetes. 1985;34:(Suppl.1):8A. 31. Bodkin NL, Hannah JS, Ortmeyer HK, Hansen BC. Central obesity in rhesus monkeys: association with hyperinsulinemia, insulin resistance, and hypertriglyceridemia? Int J Obes. 1993;17:53–61. 32. Weyer C, Hanson RL, Tataranni PA, Bogardus C, Pratley RE. A high fasting plasma insulin concentration predicts type 2 diabetes inde- pendent of insulin resistance: evidence for a pathogenic role of relative hyperinsulinemia. Diabetes. 2000;49:2094–2101. 33. Gwinup G, Elias AN. Hypothesis: insulin is responsible for the vascular complications of diabetes. Med Hypotheses. 1991;34:1–6. 34. Bodkin NL, Metzger BL, Hansen BC. Hepatic glucose production and insulin sensitivity preceding diabetes in monkeys. Am J Physiol. 1989; 256 (Endocrinol Metab):E676–E681. 35. Bodkin NL, Ortmeyer HK, Hansen BC. Diversity of insulin resistance in monkeys with normal glucose tolerance. Obes Res. 1993;1:364–370. 36. Reaven GM, Olefsky JM. Relationship between heterogeneity of insulin responses and insulin resistance in normal subjects and patients with chemical diabetes. Diabetologia. 1977;13:201–206. 37. Bogardus C, Lillioja S, Stone K, Mott D. Correlation between muscle glycogen synthase activity and in vivo insulin action in man. J Clin Invest. 1984;73:1185–1190. 38. Reaven G. Banting lecture 1988: Role of insulin resistance in human disease. Diabetes. 1988;30:1595–1607. 39. DeFronzo R, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and athero-sclerotic cardiovascular disease. Diabetes Care. 1991;14:173–194. 40. Haffner SM, Stern MP, Mitchel BD, Hazuda HP, Pugh JA, JK. Incidence of type II diabetes in Mexican Americans predicted by fasting insulin and glucose levels, obesity, and body fat distribution. Diabetes. 1990;39:283–289. 41. Masoro EJ, Mc RJM, Katz MS, McMahan CA. Dietary restriction alters characteristics of glucose fuel use. J Gerontol Biol Sci. 1992;47:B202–B208. 42. Lane M, Ingram D, Roth G. Calorie restriction in nonhuman primates: effects on diabetes and cardiovascular disease risk. Toxicol Sci. 1999; 52(Suppl.):41–48. 43. Sievers ML, RG, PH. Sequential trends in overall and cause-specific mortality in diabetic and nondiabetic Pima Indians. Diabetes Care. 1996;19:107–111. 44. Ford E, Stefano FD. Risk factors for mortality from all causes and from coronary heart disease among persons with diabetes: findings from the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study. Am J Epidemiol. 1991;133:1220–1230. 45. Standl E. Overview of the management of type 2 diabetes. Diabetes Metab Rev. 1998;14(Suppl. 1):S13–S17. 46. Chapman W. Acute gastric dilatation in Macaca mulatta and Macaca speciosa monkeys. Lab Animal Care. 1967;17:130–136. 47. Boyce L, C. Acute gastric dilatation with herniation in a rhesus monkey. Vet Med/Sm Anim Clin. 1980;75:130–131. 48. Fanton J. Acute gastric dilatation in rhesus monkeys: evaluation of abnormal gastric motility as an etiologic factor. Lab Anim Sci. 1987;37: 524. 49. S, Klein E. Systemic lupus erythematosus in a rhesus macaque. Arthritis Rheum. 1993;36:1739–1172. 50. Bardana E, Malinow M, Houghton D, et al. Diet-induced systemic lupus erythematosus (SLE) in primates. Am J Kidney Dis. 1982;1:345–352. 51. Malinow M, Bardana E, Pirofsky B, Craig S, McLaughlin P. Systemic lupus erythematosus-like syndrome in monkeys fed alfalfa sprouts: role of a nonprotein amino acid. Science. 1982;216:415–417. 52. Roecker EB, Kemnitz JW, Ershler WB, Weindruch R. Reduced immune responses in rhesus monkeys subjected to dietary restriction. Science. 2004 Sep 3;305(5689):1423-6. Aging in rhesus monkeys: relevance to human health interventions. Roth GS, Mattison JA, Ottinger MA, Chachich ME, Lane MA, Ingram DK. Progress in gerontological research has been promoted through the use of numerous animal models, which have helped identify possible mechanisms of aging and age-related chronic diseases and evaluate possible interventions with potential relevance to human aging and disease. Further development of nonhuman primate models, particularly rhesus monkeys, could accelerate this progress, because their closer genetic relationship to humans produces a highly similar aging phenotype. Because the relatively long lives of primates increase the administrative and economic demands on research involving them, new emphasis has emerged on increasing the efficient use of these valuable resources through cooperative, interdisciplinary research. PMID: 15353793 [PubMed - indexed for MEDLINE] As gerontological research continues to gain both visibility and interest within the broader scientific community, the relevance of vari-ous model systems for eventual application of findings to humans has become a critical issue. Although rodents remain the most widely used animal model for gerontology, an increasing use of invertebrates has provid-ed many new insights into aging processes, especially regarding possible longevity genes (1). Given the complexity of human physiol-ogy, however, models more phylogenetically similar to humans are needed. Advantages and Disadvantages of Nonhuman Primate Models Research using nonhuman primates can pro-vide a valuable approach for elucidating the nature and causes of aging processes observed in humans as well as evaluating potential inter-ventions. An ongoing longitudinal study of ag-ing and nutrition in rhesus monkeys (Macaca mulatta) conducted since 1987 by the National Institute on Aging (NIA), as well as studies conducted at other sites, has revealed much about aging and age-related disease in these monkeys and has shed light on the advantages and disadvantages of their use in gerontological research. Because of their genetic homology to humans (92.5 to 95%), many biological simi-larities are observed in the profile of aging. Another advantage is that rhesus monkeys are well adapted for laboratory research, including established husbandry, nutrition, breeding prac-tices, and veterinary medicine. Disadvantages of rhesus monkeys include their current limited availability, costs of procurement and mainte-nance, and genetic heterogeneity. In addition, cross-species risks of disease transmission ex-ist, and issues of animal welfare require con-stant vigilance. Research in monkeys is only as good as their physical and emotional health. The major scientific disadvantage is that rhesus monkeys are long-lived. Sexual matu-rity occurs at 3 to 5 years of age, median life-span is 25 years, and maximum life-span is 40 years (2, 3). With an estimated maxi-mum life-span of 122 years in humans (4), the rate of aging in rhesus monkeys is rough-ly three times as fast. Thus, rhesus monkeys offer a distinct advantage over long-term hu-man aging research, but longitudinal studies in these primates require a major investment of time, resources, and effort. Scope of Rhesus Monkey Research The NIA supports colonies of aging rhesus monkeys at five primate research centers in the United States (5); however, most studies con-ducted in these monkeys are cross-sectional in design. Ongoing longitudinal studies of aging and age-related disease in rhesus monkeys are being conducted at three sites: the NIA, the Wisconsin National Primate Research Center (WNPRC), and the University of land, Baltimore (UMB). Research at UMB has fo-cused on obesity and diabetes (6). With the assistance of numerous international laborato-ries, studies at the WNPRC and the NIA are evaluating the hypothesis that a nutritious low-calorie diet can retard the rate of aging (7, 8). These studies use a regimen of calorie restric-tion (CR) 30% below control levels and repre-sent the first experiments to evaluate effects of CR on aging processes in a primate species. As demonstrated in numerous studies of inverte-brate and vertebrate models, CR is the most robust and reproducible method for slowing aging, as evidenced by reduced incidence and delayed onset of age-related diseases, extension of mean and maximum life-span, increased stress resistance, and improved physiological and behavioral function (9). Emerging from years of research at many sites, abundant infor-mation on aging processes in rhesus monkeys has been generated to document parallels and relevance to human aging at organismic, tissue, cellular, and molecular levels of analysis. Aging Parallels Regarding morphology, physiology, and behavior, the profile of aging in rhesus monkeys is remarkably similar to human aging (Fig. 1). Fig.1. (A )A 19-year-old male rhesus monkey weighing 13.6 kg on the control diet. (B )A 19-year-old male rhesus monkey weighing 7.9 kg on CR for 17 years.Notably,the CR monkey generally appears smaller.(C )A 38-year-old (estimated age)male rhesus monkey weighing 6.8 kg on CR for 17 years.This monkey is one of three in the NIA study for which the exact birth date was unknown,but he & #64257;rst arrived at NIHin July 1968 with an estimated age of 4 to 8 years on the basis of body size and dentition.He was placed on CR in 1987.He died 18 April 2004 at a minimal estimated age of 40 years,but he could have been as old as 44 years,making him one of the oldest recorded of this species.This monkey had stooped posture,loss of hair,and wrinkled and sagging skin with broken blood vessels,and he exhibited arthritis,osteoporosis,and cataracts. Sensory systems decline in rhesus monkeys, including presbyopia (loss of near vision) and presbycusis (loss of high-frequency hearing) (10, 11). With ad-vancing age, they lose accommodation of the lens and develop cataracts and macular degen-eration (11). Regarding behavioral function, their general level of motor activity declines with age (12) with gradual decrements in fine-motor skills (13). Advancing age does not gen-erally affect simple discrimination learning abilities, but when demands are placed on working memory capacity, the clear age-related decline in learning and memory performance is notably similar to humans (14). Age-related changes in physiological func-tion include declines in metabolic rate and core body temperature (15). Age-related changes have not been reliably observed in cardiac func-tion, including heart rate, blood pressure, or measures of arterial stiffness, but the possible contribution of dietary sodium to these age-related changes is currently being addressed. Regarding diet, another interesting parallel to humans is an apparent decline in appetite, man-ifested as a gradual decline in food intake (16). Structural changes with aging are also evident in rhesus monkeys. Their stature becomes dimin-ished, and bone mineral density in selected sites declines with age (17). Age-related changes in cartilage occur as reduced space between verte-brae, similar to osteoarthritis in humans (18). Body composition in rhesus monkeys also parallels changes observed in humans. Their fat mass, particularly abdominal fat, increases with age, whereas lean body mass declines (19). Regarding skin quality, age-related deteriora-tion in wound healing has been documented (20). At a biochemical level, glycation of rhesus skin proteins is similar to that in humans but occurs at a predictably faster rate (21). Age-related changes in the rhesus brain have also been studied. Although overall brain mass does not decline with age as measured by weight (22), reductions have been observed in specific regional volumes with magnetic reso-nance imaging, such as the basal ganglia (23). Similar to humans, no significant loss of hip-pocampal or neocortical neurons occurs (24, 25). Behavioral deficits associated with hip-pocampal dysfunction appear to result from decrements in interneuronal signaling rather than cell death (25). Cerebral blood volume decreases with age in the hippocampal den-tate gyrus (26), and the cerebral cortex loses dendrites and arbors with age (25). Neuro-transmitter receptor and transporter binding in specific regions, including postsynaptic dopamine receptors (27) and presynaptic ve-sicular acetylcholine transporters (28), show age-related loss in the basal ganglia. Hip-pocampal cholinergic fibers are also lost with age (29), and there are notable alterations in the integrity of white matter (30). Rhesus monkeys also develop pathologi-cal characteristics of Alzheimer's disease (AD), specifically the deposition of amyloid-beta (A-beta) plaques with regional deposition similar to humans (31). A-beta plaques are associated with angiopathy (32). Although A-beta accumulates in older rhesus brains, neurofibrillary tangles, another hallmark of AD pathology, have not been observed (33). Driven by the success in mice, there is growing interest in producing transgenic monkeys in which AD and other neuro-degenerative diseases can be accurately modeled (34). Parallels also exist between rhesus mon-keys and humans regarding age-related hor-monal changes, including decreased plasma levels of melatonin (35) and dehydroepi-androsterone sulfate (DHEAs) (36). Hor-monal changes are also observed in the reproductive system. The circulating con-centration of testosterone and its pulsatile release decline with age in male rhesus monkeys (37). Rhesus females experience the perimenopausal transition similar to women at similar stages of the life-span, but the age of initiation of endocrine chang-es varies in both species (38, 39). As the perimenopausal transition progresses in women, gonadotropin levels increase. A simultaneous decrease in ovarian response results in insufficient hypothalamic-mediated stimulation of preovulatory luteiniz-ing hormone release. Ultimately, declining function of the hypothalamic-pituitary-gonadal axis culminates in menopause (40). The rhesus monkey is an appropriate model because of similarities in the perimeno-pausal transition as well as providing essential data on the consequences of peri-menopausal hormonal changes on neural systems (39). These observations are espe-cially relevant considering the controversy surrounding hormone replacement therapy, and ongoing studies will greatly elucidate clinical applications for women. Aging in human immune function is be-lieved to manifest itself, at least in part, as an increased susceptibility to infectious and au-toimmune disease and cancer. This may be related to age-related changes in cytokine production. Studies in rhesus monkeys have demonstrated age-related increases in inter-leukin (IL)– 6 and IL-10 production and de-creased interferon-gamma (41, 42), similar to re-ports in humans (43). Pathology Accompanying the biological changes that parallel aging in humans, these animals de-velop and die from similar chronic diseases. Although with normal diets rhesus monkeys do not develop severe atherosclerosis, other cardiac pathologies occur, including aortic valve calcification, interstitial fibrosis, hyper-trophy of cardiac muscle, myocardial infarc-tion, cardiac arrest, and congestive heart fail-ure (3). On high-fat diets, however, rhesus monkeys do develop atherosclerotic plaques (44). They also develop cancer, including carcinomas and sarcomas with intestinal adenocarcinomas as the most common malig-nant neoplasm (45). Additionally, endometri-osis occurs in females (46). Interestingly, although prostate gland hypertrophy occurs in males (47), prostate neoplasia is rarely observed (48). Rhesus monkeys that are fed normal laboratory diets also develop diabe-tes, with increased incidence observed on high-fat or high-calorie diets (3, 6). Consid-ered together with altered body composition, reduced bone mineral density, increased se-rum triglycerides, and increased insulin resis-tance, rhesus monkeys provide an important new model of the increasingly prevalent " metabolic syndrome " (49). Interventions Evaluation of treatments designed to retard aging, such as CR, requires a virtual " head-to- toe " approach. Aging processes should be analyzed from molecular to behavioral levels. Table 1 provides a current overview of se-lected parameters from the NIA and WNPRC Table 1.Effects of CR on selected parameters of morphology,physiology,aging,and disease in rhesus monkeys.X indicates whether CR has been shown to decrease,increase,or produce no change in the these parameters. Category/parameter Decrease Increase No change Body composition Body weight X Fat and lean mass X Trunk:Leg fat ratio X Height X Development Time to sexual maturity X Time to skeletal maturity X Metabolism Metabolic rate (short term)X Metabolic rate (long term) X Metabolic rate (long term:nighttime)X Body temperature X Thriiodothyronine (T3)X Thyroxin (T4) X Thyroid-stimulating hormone X Leptin X Endocrinology Fasting glucose/insulin X IGF-1/growth hormone X Insulin sensitivity X Age-related maintenance of melatonin and DHEAs X Testosterone;estradiol X Cardiovascular parameters Systolic blood pressure X Heart rate X Serum triglycerides X Serum HDL2B X Low-density lipoprotein interaction with proteoglycans X Lipoprotein (a)X Immunological parameters IL-6 X IL-10 X Interferon-gamma X Oxidative stress Oxidative damage to skeletal muscle X Cell biology Proliferative capacity of & #64257;broblasts X Glycation products X Functional measures Locomotor activity X Acoustic responses X rhesus monkey aging studies evaluating the effects of CR. Clearly, findings indicate bet-ter health and lower disease risk for CR monkeys compared to controls. However, both studies are still ongoing, and data are still being amassed on CR effects on aging processes, mortality, and morbidity. The widest application of rhesus monkeys has been to evaluate interventions bearing on brain aging and disease. Rhesus monkeys have shown great utility in evaluating hor-mone replacement therapies on cognition (50). In addition, successful studies of neuro-trophic factors, including nerve growth factor and glia-derived neurotrophic factor, to treat AD and Parkinson's disease, respectively, have provided a basis to evaluate these treat-ments in humans (51, 52). Rhesus monkeys have also been used to investigate gene ther-apy for neurodegenerative disorders (53). As stem cell therapies emerge for age-related brain diseases, rhesus monkeys will serve as a valuable model for evaluating their success, especially in treatment of disorders involving loss of specific neural systems, such as Par-kinson's disease. Effective gene transfer into rhesus hematopietic stem cells has already proven successful (54). In addition, monkeys have been successfully used in studies to induce breast cancer–specific antibodies (55) and prostate-specific antigen immune re-sponse (56) and to test ovarian cancer che-moprevention (57). Because rhesus monkeys can develop diet-dependent obesity and diabetes, they will also serve as highly useful models for discovering anti-obesity and antidiabetic treatments. The amino acid sequence of the nuclear receptor, peroxisome proliferator-activated receptor al-pha (PPAR-alpha), is highly homologous between humans and rhesus monkeys; thus, synthetic compounds, such as the fibrates, that can regulate lipid and lipoprotein metabolism through PPAR-alpha receptors have similar ef-fects in both species (58). Studies have fur-ther shown the potential therapeutic value of antidiabetic and anti-obesity drugs in obese or insulin-resistant rhesus monkeys (58–60). Mechanisms and Markers of Aging Insight into basic mechanisms responsible for the age-related changes described above can also be obtained. Oxidative stress pur-ported to be a major cause of aging and age-associated diseases is partially amelio-rated by CR (61). Similarly, other forms of stress, glycation, and biological disordering in general are thought to contribute to aging and are attenuated by CR (61). As reviewed above, many age-related changes in hu-mans occur in rhesus monkeys, boding well for the use of these nonhuman primates to devise interventions that delay or reduce dysfunction and pathology and possibly ex-tend the quantity and quality of life. In this regard, recent interest was fo-cused on three " biomarkers of longevity " apparently common to both CR rhesus monkeys and longer lived human males not practicing CR (62). These are lower levels of plasma insulin and body temperature, and maintenance of higher plasma levels of DHEAs. The first two have been demon-strated in CR rodents (9) as well as in monkeys, although DHEA (the sulfated form is the major species) levels are too low to evaluate in rodents. Nevertheless, cross-species similarities in CR effects on two markers and changes during normal aging in all three markers further under-score their value for both mechanistic and intervention studies. Most recently, short-term (about 6 months) 25% CR in humans of both sexes has reduced both temperature and insulin levels (63). A fundamental metabolic shift occurs in organisms on CR, from a growth and repro-ductive strategy to one of a life maintenance strategy. A drop in body temperature is evi-dence of this shift concomitant to increased protective mechanisms against various insults and pathologies, slower rate of tissue deteri-oration, and more reserve capacity observed in rodents on CR (62). Moreover, loss of insulin sensitivity during aging is probably tissue specific and secondary to changes in insulin signal transduction. Age-related de-creases in circulating DHEAs may reflect a loss of adrenal parenchymal cells and/or re-duced secretory function of surviving cells, which might affect important feedback mech-anisms. This altered hormonal status is rel-evant for current discussion of the benefits of androgen replacement therapy. Because lower insulin levels and increased insulin sensitivity is protective against diabetes and DHEAs are purported to protect against both cancer and metabolic syndrome (36), the relevance of the rhesus model for age-related disease research and possible intervention strategies for eventual human application is obvious. Conclusions Thus, we envision even more extensive use of the aging rhesus model in future re-search. Initial efforts to sequence the rhesus genome have also been initiated that will increase the value of this animal model. To aid in the further development of nonhu-man primate models of aging, the NIA and the WNPRC are developing the Primate Aging Database (PAD), which involves a multisite cooperative effort to share and analyze data in multiple species. A prelim-inary report that uses the PAD has been published demonstrating the utility of co-operative efforts to increase information in this area of research and promote efficient use of nonhuman primate resources (64). References and Notes 1.A list of genes and their aging phenotypes is available at http://sageke.sciencemag.org/cgi/genesdb. 2.R.J.Colman,J.W.Kemnitz,in Methods in Aging Research ,B.P.Yu,Ed.(CRC Press,Boca Raton,FL, 1999),pp.249 –267. 3.N.L.Bodkin,T.M.,H.K.Ortmeyer,E. ,B.C.Hansen,J.Gerontol.Biol.Sci.58A ,212 (2003). 4.More information about maximum human life-span is available at www.grg.org/calment.html. 5.U.S.NIA-supported primate research centers with colonies of aging rhesus monkeys include:Oregon Health Sciences University:http://onprc.ohsu.edu; Tulane University:www.tpc.tulane.edu;University of California,:www.crprc.ucdavis.edu;University of Washington:http://wanprc.org/WaNPRC;and Uni- versity of Wisconsin:www.primate.wisc.edu. 6.N.L.Bodkin,J.Gerontol.50A ,B142 (1995). 7.J.J.Ramsey et al .,Exp.Gerontol.35 ,1131 (2000). 8.J.A.Mattison,M.A.Lane,G.S.Roth,D.K.Ingram, Exp.Gerontol.38 ,35 (2003). 9.R.Weindruch,R.Walford,The Retardation of Aging and Disease by Dietary Restriction ( C.Thom- as,Spring & #64257;eld,IL,1988). 10.P.Torre,III,C.G.Fowler,Hear.Res.142 ,131 (2000). 11.P.L.Kaufman,L.Z.Bito,Exp.Eye Res.34 ,287 (1982). 12.T.D.Moscrip,D.K.Ingram,M.A.Lane,G.S.Roth,J.L. Weed,J.Gerontol.Biol.Sci.55 ,B373 (2000). 13.Z.Zhang et al .,J.Gerontol.55A ,B473 (2000). 14.M.L.Voytko,Neurobiol.Aging 20 ,617 (1999). 15.M.A.Lane et al .,Proc.Natl.Acad.Sci.U.S.A.93 , 4159 (1996). 16.J.A.Mattison et al .,Neurobiol.Aging ,in press. 17.A.Black et al .,Bone 28 ,295 (2001). 18.P.A.Kramer,L.L.Newell-,P.A.Simkin,J.Or- thop.Res.20 ,399 (2002). 19.S.M.Schwartz,J.W.Kemnitz,Am.J.Phys.Anthropol. 89 ,109 (1992). 20.G.S.Roth et al .,J.Gerontol.52A ,B98 (1997). 21.D.R.Sell et al .,Proc.Natl.Acad.Sci.U.S.A.93 ,485 (1996). 22.J.G.Herndon,J.Tigges,S.A.Klumpp,D.C., Neurobiol.Aging 19 ,267 (1998). 23.J.A.Matochik et al .,Neurobiol.Aging 21 ,591 (2000). 24.J.I.Keuker,P.G.Luiten,E.Fuchs,Neurobiol.Aging 24 , 157 (2003). 25.H.Duan et al .,Cereb.Cortex 13 ,950 (2003). 26.S.A.Small,M.K.Chawla,M.Bunocore,P.R.Rapp,C.A. ,Proc.Natl.Acad.Sci.U.S.A.101 ,7181 (2004). 27.E.D. et al .,J.Cereb.Blood Flow Metab.19 , 218 (1999). 28.M.L.Voytko et al .,Synapse 39 ,95 (2001). 29.M.E.Calhoun,Y.Mao,J.A.,P.R.Rapp, J.Comp.Neurol.475 ,238 (2004). 30.A.s,Prog.Brain Res.136 ,455 (2002). 31.D.L.Price et al .,Brain Pathol.1 ,287 (1991). 32.S.Sepehr et al .,Acta Neuropathol.105 ,145 (2003). 33.H.Uno et al .,Neurobiol.Aging 17 ,275 (1995). 34.S.B.Dunnett,Trends Pharmacol.Sci.22 ,211 (2001). 35.G.S.Roth,V.Lesnikov,M.Lesnikov,D.K.Ingram, M.A.Lane,J.Clin.Endo.Metab.86 ,3292 (2001). 36.M.A.Lane,D.K.Ingram,S.S.Ball,G.S.Roth,J.Clin. Endo.Metab.82 ,2093 (1997). 37.L.W.Kaler,P.Gleissman,D.L.Hess,J.Hill,Endocri- nology 119 ,566 (1986). 38.K.V.Gilardi,S.E.Shideler,C.R.Valverde,J.A. ,B.L.Lasley,Biol.Reprod.57 ,335 (1997). 39.F.L.Bellino,P.M.Wise,Biol.Reprod.68 ,10 (2003). 40.P.M.Wise,Rec.Prog.Horm.Res.57 ,235 (2002). 41.P.Mascarucci et al .,Aging Clin.Exp.Res.13 ,85 (2001). 42.M.J.Kim et al .,J.Nutr.12 ,2293 (1997). 43.L.Rink,I.Cakman,H.Kirchner,Mech.Ageing Dev. 102 ,199 (1998). 44.T.B.son,R.W.Prichard,T.M.,G.S. Petrick,K.P.Klein,JAMA 271 ,317 (1994). 45.C.R.Valverde,R.P.Tarara,S.M.Griffey,J.A., Comp.Med.50 ,540 (2000). 46.J.W.Fanton,J.G.Golden,Radiat.Res.126 ,141 (1991). 47.A.Baskerville,R.W.Cook,M.J.Dennis,M.P.Cranage, P.J.Greenaway,J.Comp.Pathol.107 ,49 (1992). 48.G.B.Hubbard,R.L.Eason,D.H.Wood,Vet.Pathol. 22 ,88 (1985). 49.S.R.Steinbaum,Prog.Cardiovasc.Dis.46 ,321 (2004). 50.P.R.Rapp,J.H.on,J.A.,J.Neurosci. 23 ,5708 (2003). 51.R.Grondin et al .,Brain 125 ,2191 (2002). 52.D.E.,J.,F.H.Gage,M.H.Tuszynski, Proc.Natl.Acad.Sci.U.S.A.96 ,10893 (1999). 53.J.H.Kordower,Ann.Neurol.53 ,S120 (2003). 54.C.E.Dunbar,J.Intern.Med.249 ,329 (2001). 55.M.Chakraborty et al .,Cancer Res.55 ,1525 (1995). 56.J.J.Kim,J.S.Yang,K.Dang,K.H.Manson,D.B. Weiner,Clin.Cancer Res.7 ,882s (2001). 57.M.Brewer et al .,Comp.Med.51 ,424 (2001). 58.D.A.Winegar et al .,J.Lipid Res.42 ,1453 (2001). 59.N.L.Bodkin,J.Pill,K.Meyer,B.C.Hansen,Horm. Metab.Res.35 ,617 (2003). 60.W.R.Oliver,Jr.et al .,Proc.Natl.Acad.Sci.U.S.A.98 , 5306 (2001). 61.G.S.Roth,D.K.Ingram,M.A.Lane,Nature Med.1 , 414 (1995). 62.G.S.Roth et al .,Science 297 ,811 (2002). 63.L.Heilbronn,paper presented at the 33rd Annual Meeting of the American Aging Association,St.Pe- tersburg,FL,4 to 7 June 2004. 64.D.A.Smucny et al .,J.Med.Primatol.33 ,48 (2004). 65.We thank the staff of the Primate Unit,Poolesville,MD, especially E.Tilmont,A.Hobbs,J.Young,T., K.Reinsfelder,A.Cisar,M.,B.White,as well as the veterinary staff of D. and R.Herbert.We also acknowledge the contributions of our international col- laborators too numerous to list here. Al Pater. Quote Link to comment Share on other sites More sharing options...
Guest guest Posted October 30, 2004 Report Share Posted October 30, 2004 Agree we may need to stay above the 5%, but 5% of what? It is interesting, I just don't know what the hexx to do with it. If a person is "lean", ok stay "lean". Regards. ----- Original Message ----- From: citpeks Sent: Friday, October 29, 2004 8:43 PM Subject: [ ] Rhesus monkeys' CR >>>From: "old542000" <apater@m...>Date: Fri Oct 29, 2004 8:45 pmSubject: Rhesus monkeys' CRThe DR monkeys were maintained on monkey chow(Purina Mills), which was calorically titrated on anindividual monkey basis to maintain a goal weight of 10to 11 kg, the weight of normal lean adult monkeys (19).This body weight is associated with a body fat rangingfrom approximately 17–24% (16,19,24). Each monkey wasweighed a minimum of once weekly, and the individualdaily chow allotment was adjusted up or down for eachmonkey depending on any change in its body weight. Thiscaloric titration usually required an increase or decrease ofone to two biscuits per day. >>>I found it interesting that CR was controlled using the body weight oflean monkeys as reference, rather than calories in the diet. Thesystem of diet adjustment based on weekly weightings seems verypractical. In humans males, 17-24% Body Fat falls in the "Fitness" (14%-17%) and "Acceptable" (18%-25%) categories, rather than in the"athlete" category (6%-13% BF).It seems significant that just maintaining a lean frame decreases therisk of death. "Results showed the risk of death for an AL fed monkeywas 2.6-fold higher than the risk of death for a DR monkeyof the same age." The results imply that humans keeping %BF in the 15% range wouldalready have a lower risk of death, but we knew that, didn't we?However, it is nice to know that you don't have to get down to 5% BFto enjoy the benefits.Tony Quote Link to comment Share on other sites More sharing options...
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