Strategy for identifying biomarkers of aging in long-lived species

If effective anti-aging interventions are to be identified for human application, then the development of reliable and valid biomarkers of aging are essential for this progress. Despite the apparent demand for such gerotechnology, biomarker research has become a controversial pursuit. Much of the controversy has emerged from a lack of consensus on terminology and standards for evaluating the reliability and validity of candidate biomarkers. The initiation of longitudinal studies of aging in long-lived non-human primates has provided an opportunity for establishing the reliability and validity of biomarkers of aging potentially suitable for human studies. From the primate study initiated in 1987 at the National Institute on Aging (NIA), the following criteria for defining a biomarker of aging have been offered: (1) significant cross-sectional correlation with age; (2) significant longitudinal change in the same direction as the cross-sectional correlation; (3) significant stability of individual differences over time. These criteria relate to both reliability and validity. However, the process of validating a candidate biomarker requires a greater standard of proof. Ideally, the rate of change in a biomarker of aging should be predictive of lifespan. In short-lived species, such as rodents, populations differing in lifespan can be identified, such as different strains of rodents or groups on different diets, such as those subjected to calorie restriction (CR), which live markedly longer. However, in the NIA primate study, the objective is to demonstrate that CR retards the rate of aging and increases lifespan. In the absence of lifespan data associated with CR in primates, validation of biomarkers of aging must rely on other strategies of proof. With this challenge, we have offered the following strategy: If a candidate biomarker is a valid measure of the rate of aging, then the rate of age-related change in the biomarker should be proportional to differences in lifespan among related species. Thus, for example, the rate of change in a candidate biomarker of aging in chimpanzees should be twice that of humans (60 vs 120 years maximum lifespan); in rhesus monkeys three times that of humans (40 vs 120 years maximum lifespan). The realization of this strategy will be aided by developing a primate aging database, a project that was recently launched in cooperation with the NIA, the National Center for Research Resources, and the University of Wisconsin Regional Primate Research Center.     

Life-long caloric restriction reveals biphasic and dimorphic effects on bone metabolism in rodents

Caloric restriction (CR) extends the lifespan of various organisms and slows the onset of age-related disorders; however, little is known about the long-term effects of CR per se on bone. In the present study, we have examined the effects of life-long CR vs. ad libitum (AD) feeding, mainly on the trabecular bone of proximal tibiae in male C57BL/6 mice and F344 rats. Micro-computed tomography scanning of tibiae revealed that CR for 3-9 months caused a substantial decrease in three-dimensional bone volume with structural derangements. Bone histomorphometry revealed the reduced bone mass was due mainly to suppression of bone formation. In db/db mice with defective leptin receptor, CR was unable to decrease bone mass and suppress bone formation. The effect of CR on bone mass was inhibited by administration of a beta-adrenergic blocker, propranolol. Thus, CR may regulate bone formation through leptin signaling and elevated sympathetic nervous tone. Interestingly, the difference in bone volume between the CR and AD groups disappeared after 1 yr of age, and mice and rats on an additional extension of CR to natural death maintained higher bone mass than the AD groups, with reduced bone turnover, suggesting that CR slows skeletal aging by regulating the rate of bone turnover. This is the first report, to our knowledge, that has examined the effects of lifelong CR on bone metabolism and trabecular microstructure and documents its contrasting effects during maturation vs. the postmaturational, involutional period.     

Caloric restriction <Emphasis Type="Italic">versus</Emphasis> drug therapy to delay the onset of aging diseases and extend life

There are two firmly established methods of prolonging life. Calorie restriction (CR) using nutrient-rich diets to prolong life in lower animals, and life saving medications in humans to delay the development of the major diseases of middle and old age. These two approaches have different mechanisms of action. In rats, CR at 40% below ad libitum intake begun soon after weaning and continued until death, reduces body weight by about 40% and increases lifespan. There have been no lifelong CR studies performed on humans. However, in healthy adult human subjects about 20% CR over a period of 2–15 years, lowers body weight by about 20% and decreases body mass index (BMI) to about 19. This CR treatment in humans reduces blood pressure and blood cholesterol to a similar extent as the specific drugs used to delay the onset of vascular disease and so extend human life. These same drugs may act by mechanisms that overlap with some of the mechanisms of CR in retarding these pathologies and thus may have similar antiaging and life prolonging actions. Such drugs may be regarded as CR mimetics which inhibit the development of certain life shortening diseases, without the need to lower calorie intake. In developed countries, better medical care, drug therapy, vaccinations, and other public health measures have extended human life by about 30 years during the 20th century without recourse to CR, which is so effective in the rat. The percentage gain in human life expectancy during the 20th century is twice that achieved by CR in rat survival. However, rat longevity studies now use specific pathogen-free animals and start CR after weaning or later, thereby excluding deaths from infectious diseases and those associated with birth and early life. There is a need to develop CR mimetics which can delay the development of life-threatening diseases in humans. In the 21st century due to the human epidemic of overeating with a sedentary lifestyle, it may necessary to utilize CR to counter the aging effects of overweight. Since the greatest life-extending effects of CR in the rodent occur when started early in life, long-term antiaging therapy in humans should be initiated soon after maturity, when physiological systems have developed optimally.     

Life-long caloric restriction does not alter the severity of age-related osteoarthritis

Chronic adipose tissue inflammation and its associated adipokines have been linked to the development of osteoarthritis (OA). It has been shown that caloric restriction may decrease body mass index and adiposity. The objectives of this study were to investigate the effect of lifelong caloric restriction on bone morphology, joint inflammation, and spontaneously occurring OA development in aged mice. C57BL/NIA mice were fed either a calorie-restricted (CR) or ad libitum (AL) diet starting at 14 weeks of age. All mice were sacrificed at 24 months of age. Adipose tissue and knee joints were then harvested. Bone parameters of the joints were analyzed by micro-CT. OA and joint synovitis were determined using histology and semiquantitative analysis. Lifelong caloric restriction did not alter the severity of OA development in C57BL/NIA aged mice, and there was no difference in the total joint Mankin score between CR and AL groups (p = 0.99). Mice also exhibited similar levels of synovitis (p = 0.54). The bone mineral density of the femur and the tibia was comparable between the groups with a small increase in cancellous bone volume fraction in the lateral femoral condyle of the CR group compared with the AL group. Lifelong caloric restriction did not alter the incidence of OA or joint synovitis in C57BL/NIA mice, indicating that a reduction of caloric intake alone was not sufficient to prevent spontaneous age-related OA. Nonetheless, early initiation of CR continued throughout a life span did not negatively impact bone structural properties.     

Dietary Approaches that Delay Age-Related Diseases

Reducing food intake in lower animals such as the rat decreases body weight, retards many aging processes, delays the onset of most diseases of old age, and prolongs life. A number of clinical trials of food restriction in healthy adult human subjects running over 2–15 years show significant reductions in body weight, blood cholesterol, blood glucose, and blood pressure, which are risk factors for the development of cardiovascular disease and diabetes. Lifestyle interventions that lower energy balance by reducing body weight such as physical exercise can also delay the development of diabetes and cardiovascular disease. In general, clinical trials are suggesting that diets high in calories or fat along with overweight are associated with increased risk for cardiovascular disease, type 2 diabetes, some cancers, and dementia. There is a growing literature indicating that specific dietary constituents are able to influence the development of age-related diseases, including certain fats (trans fatty acids, saturated, and polyunsaturated fats) and cholesterol for cardiovascular disease, glycemic index and fiber for diabetes, fruits and vegetables for cardiovascular disease, and calcium and vitamin D for osteoporosis and bone fracture. In addition, there are dietary compounds from different functional foods, herbs, and neutraceuticals such as ginseng, nuts, grains, and polyphenols that may affect the development of age-related diseases. Long-term prospective clinical trials will be needed to confirm these diet—disease relationships. On the basis of current research, the best diet to delay age-related disease onset is one low in calories and saturated fat and high in wholegrain cereals, legumes, fruits and vegetables, and which maintains a lean body weight. Such a diet should become a key component of healthy aging, delaying age-related diseases and perhaps intervening in the aging process itself. Furthermore, there are studies suggesting that nutrition in childhood and even in the fetus may influence the later development of aging diseases and lifespan.     

Chronic caloric restriction partially protects against age-related alteration in serum metabolome

Calorie restriction (CR) remains the most robust metabolic intervention to extend lifespan and improve healthspan in several species. Using global and targeted mass spectrometry-based metabolomics approaches, here we show that chronic CR prevents age-related changes in specific metabolic signatures. Global metabolomic analysis using ultra-performance liquid chromatography–tandem mass spectrometry detected more than 7,000 metabolites in sera from ad-libitum-fed young, aged, and aged C57BL/6 mice maintained on 40 % CR. Multivariate statistical analysis of mass spectrometry data revealed a clear separation among the young, aged, and aged–CR mice demonstrating the potential of this approach for producing reliable metabolic profiles that discriminate based on age and diet. We have identified 168 discriminating features with high statistical significance (p ≤ 0.001) and validated and quantified three of these metabolites using targeted metabolite analysis. Calorie restriction prevented the age-related alteration in specific metabolites, namely lysophosphatidylcholines (16:1 and 18:4), sphingomyelin (d18:1/12:0), tetracosahexaenoic acid, and 7α-dihydroxy-4-cholesten-3-one, in the serum. Pathway analysis revealed that CR impacted the age-related changes in metabolic byproducts of lipid metabolism, fatty acid metabolism, and bile acid biosynthesis. Our data suggest that metabolomics approach has the potential to elucidate the metabolic mechanism of CR’s potential anti-aging effects in larger-scale investigations.

Electronic supplementary material

The online version of this article (doi:10.1007/s11357-012-9430-x) contains supplementary material, which is available to authorized users.     

Calorie restriction and skeletal mass in rhesus monkeys (Macaca mulatta): evidence for an effect mediated through changes in body size

Little is known regarding the effects of prolonged calorie restriction (CR) on skeletal health. We investigated long-term (11 years) and short-term (12 months) effects of moderate CR on bone mass and biochemical indices of bone metabolism in male rhesus monkeys across a range of ages. A lower bone mass in long-term CR monkeys was accounted for by adjusting for age and body weight differences. A further analysis indicated that lean mass, but not fat mass, was a strong predictor of bone mass in both CR and control monkeys. No effect of short-term CR on bone mass was observed in older monkeys (mean age, 19 years), although young monkeys (4 years) subjected to short-term CR exhibited slower gains in total body bone density and content than age-matched controls. Neither biochemical markers of bone turnover nor hormonal regulators of bone metabolism were affected by long-term CR. Although osteocalcin concentrations were significantly lower in young restricted males after 1 month on 30% CR in the short-term study, they were no longer different from control values by 6 months on 30% CR.     

Caloric restriction reduces age-related pseudocapillarization of the hepatic sinusoid

Age-related changes in the hepatic sinusoid, called pseudocapillarization, may contribute to the pathogenesis of dyslipidemia. Caloric restriction (CR) is a powerful model for the study of aging because it extends lifespan. We assessed the effects of CR on the hepatic sinusoid to determine whether pseudocapillarization is preventable and hence a target for the prevention of age-related dyslipidemia. Livers from young (6 months) and old (24 months) CR and ad libitum fed (AL) F344 rats were examined using electron microscopy and immunohistochemistry. In old age, there was increased thickness of the liver sinusoidal endothelium and reduced endothelial fenestration porosity. In old CR rats, endothelial thickness was less and fenestration porosity was greater than in old AL rats. Immunohistochemistry showed that CR prevented age-related decrease in caveolin-1 expression and increase in peri-sinusoidal collagen IV staining, but did not alter the age-related increase of von Willebrand's factor. CR reduces age-related pseudocapillarization of the hepatic sinusoid and correlates with changes in caveolin-1 expression.     

Calorie restriction attenuates age-related alterations in the plasma membrane antioxidant system in rat liver

Aging is associated with increased production of reactive oxygen species and oxidation-induced damage to intracellular structures and membranes. Caloric restriction (CR) is the only non-genetic method proven to extend lifespan in mammals. Although the mechanisms of CR remain to be clearly elucidated, reductions in oxidative stress have been shown to increase lifespan in several model systems. Oxidative stress can be attenuated by CR. Mitochondria and plasma membrane (PM) are normal sources of free radicals. The PM has a trans-membrane redox system that provides electrons to recycle lipophilic antioxidants, such as alpha-tocopherol and coenzyme Q (CoQ). The idea developed in this study is that the PM is intimately involved in cellular physiology controlling the relationship of the cell to its environment. PM is the key for protecting cellular integrity during aging. Specifically, we have investigated age-related alterations and the effects of CR in the trans-PM redox (antioxidant) system in rat liver. We found that age-related declines in the ratio of CoQ(10)/CoQ(9) and alpha-tocopherol in liver PM were attenuated by CR compared to those fed ad libitum (AL). CoQ-dependent NAD(P)H dehydrogenases were increased in CR old rat liver PMs. As a consequence, the liver PM of CR old rats was more resistant to oxidative stress-induced lipid peroxidation than AL rats. Thus, our results suggest that CR induces a higher capacity to oxidize NAD(P)H in the PM of old rat livers and as a result, a higher resistance to oxidative stress-induced damage.     

The role of calorie restriction and SIRT1 in prion-mediated neurodegeneration

A central focus of aging research is to determine how calorie restriction (CR) extends lifespan and delays diseases of aging. SIRT1, the mammalian ortholog of Sir2 in yeast, is a longevity factor which mediates dietary restriction in diverse species. In addition, SIRT1 plays a protective role in several models of neurodegenerative disease. We tested the role of SIRT1 in mediating the effects of CR in a mouse model of prion disease. Prion diseases are protein misfolding disorders of the central nervous system with many similarities to other neurodegenerative diseases, including deposition of aggregated protein, gliosis, and loss of synapses and neurons. We report that the onset of prion disease is delayed by CR and in the SIRT1 KO mice fed ad libitum. CR exerts no further effect on the SIRT1 KO strain, suggesting the effects of CR and SIRT1 deletion are mechanistically coupled. In conjunction, SIRT1 is downregulated in certain brain regions of CR mice. The expression of PrP mRNA and protein is reduced in the brains of CR mice and in SIRT1 knockout mice, suggesting a possible mechanism for the delayed onset of disease, as PrP levels are a critical determinant of how quickly mice succumb to prion disease. Surprisingly, CR greatly shortens the duration of clinical symptoms of prion disease and ultimately shortens lifespan of prion-inoculated mice in a manner that is independent of SIRT1. Taken together, our results suggest a more complex interplay between CR, SIRT1, and neurodegenerative diseases than previously appreciated.     

Effect of a caloric restriction regimen on the angiogenic capacity of aorta and on the expression of endothelin-1 during ageing

Ageing is accompanied by impaired angiogenesis, as well as by a deficient expression of several angiogenic growth factors and the alteration of endothelial functions. Caloric restriction (CR) is the only intervention that can extend lifespan and retard age-related-decline functions in mammals by reducing the rate of ageing and the progression of the associated diseases. Herein, we have investigated the effects of ageing and of a caloric restriction regimen (mild or severe) on the angiogenic response and on the expression of endothelin-1 (ET-1) in the aorta of male 3-, 12- or 24-month-old Sprague-Dawley rats fed ad libitum (AL), fed ad libitum and fasted 1 day a week (mild CR) or fasted every other in alternate days (severe CR). Our findings, using the rat aorta ring assay, show that the angiogenic capacity of aorta decreases with ageing in the oldest rats only. Furthermore, caloric restriction counteracts the age-related changes caloric restrictions actually give raise to a similar recovery. Interestingly, the mRNA ET-1 levels as well as ET-1 expression in aorta sprouting decreases both in middle and in aged animals. Mild and severe caloric restriction regimens prevents ET-1 changes.     

Delay of T cell senescence by caloric restriction in aged long-lived nonhuman primates

Caloric restriction (CR) has long been known to increase median and maximal lifespans and to decreases mortality and morbidity in short-lived animal models, likely by altering fundamental biological processes that regulate aging and longevity. In rodents, CR was reported to delay the aging of the immune system (immune senescence), which is believed to be largely responsible for a dramatic increase in age-related susceptibility to infectious diseases. However, it is unclear whether CR can exert similar effects in long-lived organisms. Previous studies involving 2- to 4-year CR treatment of long-lived primates failed to find a CR effect or reported effects on the immune system opposite to those seen in CR-treated rodents. Here we show that long-term CR delays the adverse effects of aging on nonhuman primate T cells. CR effected a marked improvement in the maintenance and/or production of na?ve T cells and the consequent preservation of T cell receptor repertoire diversity. Furthermore, CR also improved T cell function and reduced production of inflammatory cytokines by memory T cells. Our results provide evidence that CR can delay immune senescence in nonhuman primates, potentially contributing to an extended lifespan by reducing susceptibility to infectious disease.     

Caloric restriction and antiaging effects

Caloric restriction (CR) is widely used to study aging processes. It is a simple and highly reproducible method for delaying the aging process, preventing the onset of aging-related diseases and extending average or maximum lifespan. However, the mechanism underlying these effects of CR is still not clear. CR can inhibit growth, reduce body size and maintain a low body temperature. At the same time, there is a measurable decrease in the volume of adipose tissue, hyperglycemia and hyperinsulinemia, accompanied by modifications of lipid and energy metabolism and increased resistance to endogenous and extraneous stress. The metabolic changes induced by dietary restriction, the inhibition of fat deposition in nonadipose tissue and the effects on signal transduction are considered the most likely candidates for mechanisms underlying the effects of CR.     

Caloric restriction delays aging-induced cellular phenotypes in rhesus monkey skeletal muscle

Sarcopenia is the age-related loss of skeletal muscle mass and function and is characterized by a reduction in muscle mass and fiber cross-sectional area, alterations in muscle fiber type and mitochondrial functional changes. In rhesus monkeys, calorie restriction (CR) without malnutrition improves survival and delays the onset of age-associated diseases and disorders including sarcopenia. We present a longitudinal study on the impact of CR on early stage sarcopenia in the upper leg of monkeys from ~ 16 years to ~ 22 years of age. Using dual-energy X-ray absorptiometry we show that CR delayed the development of maximum muscle mass and, unlike Control animals, muscle mass of the upper leg was preserved in CR animals during early phase sarcopenia. Histochemical analyses of vastus lateralis muscle biopsies revealed that CR opposed age-related changes in the proportion of Type II muscle fibers and fiber cross-sectional area. In contrast the number of muscle fibers with mitochondrial electron transport system enzyme abnormalities (ETS^ab) was not significantly affected by CR. Laser capture microdissection of ETS^ab fibers and subsequent PCR analysis of the mitochondrial DNA revealed large deletion mutations in fibers with abnormal mitochondrial enzyme activities. CR did not prevent stochastic mitochondrial deletion mutations in muscle fibers but CR may have contributed to the maintenance of affected fibers.     

Beyond the rodent model: Calorie restriction in rhesus monkeys

Lifespan extension and reduction of age-related disease by calorie restriction (CR) are among the most consistent findings in gerontological research. The well known effects of CR have been demonstrated many times in rodents and other short-lived species. However, effects of CR on aging in longer-lived species, more closely related to humans, were unknown until recently. Studies of CR and aging using nonhuman primates (rhesus monkeys) were begun several years ago at the National Institute on Aging, the University of Wisconsin-Madison, and the University of Maryland. These studies are beginning to yield useful data regarding the effects of this nutritional intervention in primates. Several studies from these ongoing investigations have shown that rhesus monkeys on CR exhibit physiological responses to CR that parallel findings in rodents. In addition, several potential biomarkers of aging are being evaluated and preliminary findings suggest the possibility that CR in rhesus monkeys could slow the rate of aging and reduce age-related disease, specifically diabetes and cardiovascular disease. It will be several years before conclusive proof that CR slows aging and extends life span in primates is established, however, results from these exciting studies suggest the possibility that the anti-aging effects of CR reported in rodents also occur in longer-lived species such as nonhuman primates, strenghtening the possibility that this nutritional intervention will also prove beneficial in longer-lived species, including humans.     

Dopamine and serotonin systems in human and rodent brain: effects of age and neurodegenerative disease

The nonpathological age-related changes in the dopamine- and serotonin-containing neurotransmitter systems in human and rodent brain are reviewed. The dopamine system exhibits age-related declines both presynaptically and postsynaptically. Presynaptically, both the levels of dopamine and the number of midbrain dopamine-containing neurons decline by up to 50% at advanced ages in the absence of neurological disease. Postsynaptically, the density of D-2 dopamine receptors decreases by 40%, while D-1 dopamine receptors either increase (man) or remain stable (rodents). Additional reductions of dopamine levels and D-2 receptors have been reported in Alzheimer's disease (AD), but these changes are relatively small, and not consistently observed. The levels of serotonin appear stable during normal aging, and presynaptic markers such as (3H)imipramine binding may actually increase. In human brain, the two major classes of serotonin receptor (S-1 and S-2) decrease by 30 to 50% over the lifespan. In AD, both presynaptic and postsynaptic markers of the serotonin system are reduced, including a loss of the serotonin-containing raphe neurons. The additional loss of serotonin receptors in AD approaches 80% when compared with young normals. A hypothesis is presented to explain the typically young age at onset of schizophrenia (usually before 30 years of age) and the older age at onset of parkinsonism (rarely before 50 years of age) within the context of normal age-related declines in the dopamine system occurring in the absence of neurological disorders. The possibility that chronic cocaine abuse might accelerate the development of parkinsonism is discussed.     

Maximal power across the lifespan

BACKGROUND: Previous investigators have reported that maximal power increases during growth and decreases with aging. These age-related differences have been reported to persist even when power is scaled to body mass or muscle size. We hypothesized that age-related differences in maximal power were primarily related to differences in muscle size and fiber-type distribution rather than to age per se. METHODS: Maximum cycling power (Pmax) and optimal pedaling rate (Vopt, a surrogate measure for muscle fiber type) were determined for 195 boys and men, 8-70 years of age, by using inertial load cycle ergometry. Anthropometric dimensions were used to estimate lean thigh volume (LTVest) of all subjects, and magnetic resonance imagery was used to determine thigh and hip muscle volume (MRIvol) for 24 subjects. RESULTS: Pmax was highly related to the product of LTVest and Vopt (LTVest X Vopt; r2 = .83). Multiple regression revealed that Pmax was significantly related to both LTVest x Vopt and age (R2 = .84). Power scaled by LTVest X Vopt was stable during growth and exhibited a small but significant decrease with aging. MRIvol was highly correlated with LTVest, and the ratio of LTVest to MRIvol was independent of age. CONCLUSIONS: These results suggest that muscle volume and optimal pedaling rate are the main determinants of maximal power across the lifespan and that the contractile properties of muscle are developed early in childhood and remain nearly intact late into the lifespan.     

Recent advances in calorie restriction research on aging

The extension of both median and maximum lifespan and the suppression of age-related diseases in laboratory animals by reduced food intake, i.e., calorie restriction (CR) are regarded as hallmarks of CR's anti-aging action. The diverse efficacy of CR to counteract aging effects and its experimental reproducibility has made it the gold standard of many aging intervention studies of recent years. Although CR originally was used as a tool to perturb the aging process of laboratory animals as to uncover clues of underlying mechanisms of aging processes, current CR research interests have shifted to the retardation of aging-related functional decline and the prevention of age-related diseases. Advances in CR research on non-human primates and recent endeavors using human subjects offer a promising outlook for CR's beneficial effects in healthy human aging.     

Effects of calorie restriction on chromosomal stability in rhesus monkeys (<Emphasis Type="Italic">Macaca mulatta</Emphasis>)

The basic tenet of several theories on aging is increasing genomic instability resulting from interactions with the environment. Chromosomal aberrations have been used as classic examples of increasing genomic instability since they demonstrate an increase in numerical and structural abnormalities with age in many species including humans. This accumulating damage may augment many aging processes and initiate age-related diseases, such as neoplasias. Calorie restriction (CR) is one of the most robust interventions for reducing the frequency of age-related diseases and for extending life span in many short-lived organisms. However, the mechanisms for the anti-aging effects of CR are not yet well understood. A study of rhesus monkeys was begun in 1987 to determine if CR is also effective in reducing the frequency of age-related diseases and retarding aging in a long-lived mammal. Male monkeys were begun on the diet in 1987, and females were added in 1992 to examine a possible difference in response to CR by sex. The CR monkeys have been maintained for over 10 years on a low-fat nutritional diet that provides a 30% calorie reduction compared to a control (CON) group. Because of the greater similarity of nonhuman primates to humans in life span and environmental responses to diet compared with those of rodents, the rhesus monkey provides an excellent model for the effects of CR in humans. This study examined the effects of CR on chromosomal instability with aging. Significant age effects were found in both CR and CON groups for the number of cells with aneuploidy: old animals had a higher loss and a higher gain than young animals. However, there was no effect of age on chromosomal breakage or structural aberrations in either diet group. Diet had only one significant effect: the CR group had a higher frequency of chromatid gaps than did the CON group. CR, implemented in adult rhesus monkeys, does not have a major effect on the reduction of numerical or structural aberrations related to aging.     

Human growth hormone replacement in adult hypopituitary patients: long-term effects on body composition and lipid status--3-year results from the HypoCCS Database

The Hypopituitary Control and Complications Study is an international surveillance study evaluating efficacy and safety of GH therapy of adult GH-deficient patients in clinical practice. The present report examined baseline data from 1,123 adult onset (AO) and 362 childhood onset (CO) patients, as well as efficacy in 242 patients who had completed 3 yr of GH treatment. At study entry, mean height, body mass index, waist to hip ratio, and lean body mass were significantly (P < 0.001 for each) lower in CO compared with AO patients. After 3 yr on GH, lean body mass was significantly increased in AO males and females and CO males but not CO females, whereas fat mass was significantly decreased in AO males only. Serum total cholesterol was decreased in females (-0.32 +/- 1.00 mmol/liter; P = 0.045) and males (-0.36 +/- 0.96 mmol/liter; P = 0.004). High-density lipoprotein (HDL) cholesterol was increased for females (0.10 +/- 0.26 mmol/liter; P = 0.026) and males (0.10 +/- 0.34 mmol/liter; P = 0.022). The low-density lipoprotein/HDL ratio was decreased in AO males (-0.93 +/- 2.00; P = 0.003), AO females (-0.65 +/- 0.74; P < 0.001), and CO females (-0.69 +/- 0.76; P = 0.038), but the decrease in CO males was not significant (-0.84 +/- 2.85; P = 0.273). In AO patients, lean body mass increase from baseline was greatest in the those younger than 40 yr old, less but still significant in the middle group (40-60 yr) and unchanged in older (>60 yr) patients; conversely, decreases in the low-density lipoprotein/HDL ratio were small and not significant in the younger patients but greater and significant in the middle and older age groups. During the 3-yr treatment, 114 (7.7%) patients discontinued, including 9 (0.6%) for tumor recurrences, 9 (0.6%) for neoplasia, and 9 (0.6%) for side effects. Therefore, these observational data showed significant long-term efficacy of adult GH replacement therapy on body composition and lipid profiles and indicate that age is an important predictor of response.