Caloric Restriction and Caloric Restriction Mimetics: Current Status and Promise for the Future

Dietary caloric restriction is the most reproducible means of extending longevity and maintaining health and vitality. It has been shown to be relevant to a wide rage of species, including primates. Examination of key markers of the calorically restricted phenotype, such as plasma insulin, dehydroepiandrosterone sulfate, and body temperature, suggest that they may predict longevity in humans as well. However, most people would be unwilling or unable to adopt the 30% to 40% reduction in food intake necessary to achieve optimal health and longevity benefits. For this reason, a number of laboratories are pursuing caloric restriction mimetics: ways to achieve the benefits of restriction without eating less. This approach will undoubtedly remain a major focus of biogerontolgy for the foreseeable future.     

Age-related changes in cytokine production by leukocytes in rhesus monkeys

Using a variety of experimental rodent and human models, age-related alterations in cytokine production by immune cells have been described extensively. While the precise mechanism(s) responsible for such age-related changes in cytokine responses remain unclear, it seems likely that these changes may have a significant effect on immune cell function. In an attempt to clarify such changes in aging primates, we examined cytokine production by white cells derived from a controlled colony of rhesus monkeys (Macaca mulatta). Non-fractionated whole blood and peripheral blood mononuclear cells (PBMCs) were obtained from male monkeys of different ages (6-28 years), and were subsequently evaluated for their ability to express mRNA and protein for the cytokines, IL-10, IL-6, IFNgamma, IL-1beta, and TNFalpha, following in vitro stimulation with polyclonal mitogens. Our results suggest that white blood cells derived from aged rhesus monkeys exhibit a significant increase in their ability to produce the Th2-associated cytokine, IL-10, upon stimulation with lipopolysaccharide (LPS) when compared to white cells derived from younger counterparts. Similarly, a significant age-related decrease in the expression of the Th1-associated cytokine, IFNgamma, was also observed using phytohemagglutinin (PHA)-stimulated PBMCs. No significant age-related differences in the production of IL-1beta or TNFalpha were observed in response to any stimulation, but there was limited evidence of an age-related increase in IL-6 production. Overall, our results suggest that a possible systemic change from a Th0/Th1 to a Th2-like cytokine profile occurs in circulating leukocytes derived from aging primates. We believe that such age-related alterations in cytokine production may play a role in the reduced immune responses observed in elderly human populations.     

Autoregulation of the gonadotropin-releasing hormone (GnRH) system during puberty: effects of antagonistic versus agonistic GnRH analogs in a female rat model

To address whether gonadotropin-releasing hormone (GnRH) regulates its own expression and the expression of its receptor in the hypothalamus and ovary, we treated five groups of prepubertal/peripubertal female rats from postnatal days 25-36 with either the GnRH agonist triptorelin (TRIP) or the GnRH antagonist cetrorelix (CET), each 10 or 100 microgram/day, or a placebo. We compared their effects regarding pubertal development, serum gonadotropins and the expression of GnRH and GnRH-receptor in the hypothalamus, pituitary, ovary and uterus. Onset of puberty was determined by vaginal opening, and expression levels of GnRH and GnRH-receptor were determined using either quantitative real-time PCR or competitive RT-PCR. Onset of puberty was retarded by both analogs but CET (100 microgram/day) inhibited while TRIP (10 and 100 microgram/day) stimulated serum gonadotropins (P<0.05). The expression of GnRH in the preoptic area did not show significant differences among the treatment groups but ovarian GnRH mRNA levels were significantly stimulated by CET (100 microgram/day). GnRH mRNA could not be detected in the uterus by either real-time PCR or competetive RT-PCR. The GnRH-receptor expression in the hypothalamus (preoptic area and mediobasal hypothalamus) did not vary among any of the groups, whereas in the pituitary GnRH-receptor mRNA levels were stimulated by TRIP (10 microgram/day) but inhibited by CET (100 microgram/day). In contrast, in the ovary GnRH-receptor mRNA levels were inhibited by both TRIP (100 microgram/day) and CET (100 microgram/day). Interestingly, the GnRH-receptor was even expressed in the uterus where it was strongly stimulated by both CET and TRIP in a dose-related manner. This shows that in addition to their different pituitary effects, the GnRH analogs cetrorelix and triptorelin exert different actions at the hypothalamic, ovarian and uterine level. This study also demonstrates an organ-specific regulation of GnRH and GnRH-receptor gene expression which is likely part of a local autoregulatory system. We conclude that the ovarian and uterine effects of GnRH analogs must be considered in addition to their known pituitary effects when deciding which GnRH analog is most suitable for treating precocious puberty.     

Influence of left ventricular function on outcome of patients treated with implantable defibrillators.

BACKGROUND. The outcomes of patients treated with implantable defibrillators were compared between patients with left ventricular ejection fraction greater than or equal to 30% and less than 30%. METHODS AND RESULTS. Of 68 consecutive patients treated with implantable defibrillators, 40 patients (group 1) had left ventricular ejection fraction greater than or equal to 30%, and 28 patients (group 2) had left ventricular ejection fraction less than 30%. Sudden death, surgical mortality, nonsudden arrhythmia-related death (death within 24 hours after an arrhythmic event despite initial termination of the arrhythmia by the implantable defibrillator), total arrhythmia-related death (including sudden death, surgical death, and nonsudden arrhythmia-related death), and total cardiac death were compared between the two groups. Surgical mortality was 4.4% (0% in group 1, 11% in group 2). During the follow-up of 31 +/- 27 months, actuarial survival rates free of events were 97%, 97%, and 97% in group 1 and 96%, 91%, and 82% in group 2 at 12, 24, and 36 months, respectively, for sudden death (p = NS); 97%, 97%, and 97% in group 1 and 85%, 81%, and 72% in group 2 at 12, 24, and 36 months, respectively, for sudden death and surgical mortality (p less than 0.05); 97%, 97%, and 97% in group 1 and 82%, 78%, and 70% in group 2 at 12, 24, and 36 months, respectively, for total arrhythmia-related death (p less than 0.05); and 95%, 95%, and 95% in group 1 and 82%, 69%, and 57% in group 2 at 12, 24, and 36 months, respectively, for total cardiac death (p less than 0.05). Four (57%) of seven nonsudden cardiac deaths during the initial 36-month follow-up period were causally related to arrhythmia (three surgical deaths and one arrhythmia-related nonsudden death). CONCLUSIONS. The outcome of patients treated with implantable defibrillators is strongly influenced by the degree of left ventricular dysfunction. In group 1 patients, surgical mortality, sudden death, and total cardiac death are rare. In group 2, sudden death rate may not be markedly different from that of group 1 patients. However, the risk of therapy (surgical mortality) is high. Many nonsudden cardiac deaths are causally related to arrhythmia (surgical mortality or nonsudden arrhythmia-related death). Therefore, the survival rate free of total arrhythmia-related death is significantly lower in group 2 (70% versus 97% in group 1 at 3 years). Further studies are needed to determine the roles of defibrillator therapy and other therapies in various clinical settings.     

Virological fitness of HIV in patients with resistance to enfuvirtide

Resistance to the HIV fusion inhibitor enfuvirtide is associated with mutations in the first heptad repeat region of gp41, but little is known of their impact on replicative fitness in vivo. We followed seven patients undergoing salvage therapy that included enfuvirtide in order to document the temporal generation of genotypic and phenotypic resistance in parallel with replicative fitness. Resistance to enfuvirtide was not associated with decreased replicative fitness of HIV strains infecting these patients.     

Predictors of overall quality of care provided to vulnerable older people

OBJECTIVES: Prior research shows that the quality of care provided to vulnerable older persons is suboptimal, but little is known about the factors associated with care quality for this group. In this study, the influences of clinical conditions, types of care processes, and sociodemographic characteristics on the quality of care received by vulnerable older people were evaluated. DESIGN: Observational cohort study. SETTING: Two senior managed care plans. PARTICIPANTS: Three hundred sixty-two community-dwelling patients aged 65 and older identified as vulnerable by the Vulnerable Elder Survey (VES-13). MEASUREMENTS: Outcome variable: patients' observed-minus-expected overall quality score. Predictor variables: types of care processes, types and number of clinical conditions, sex, age, VES-13 score (composite score of function and self-rated health), income, education, mental health status, and number of quality indicators triggered. RESULTS: Patients whose conditions required more history-taking, counseling, and medication-prescribing care processes and patients with diabetes mellitus received lower-than-expected quality of care. A greater number of comorbid conditions was associated with higher-than-expected quality of care. Age, sex, VES-13 score, and other sociodemographic variables were not associated with quality of care. CONCLUSION: Complexity, vulnerability, and age do not predispose older persons to receive poorer-quality care. In contrast, older patients whose care requires time-consuming processes such as history taking and counseling are at risk for worse quality of care and should be a target for intervention to improve care.     

Effect of age on sensitivity to pain and brain opiate receptors

Age-related differences in sensitivity to pain as induced by heat and electrical shock were seen among groups of rats; 2-3, 6-12, and 24 months of age. These are differences were at least partially obliterated by naloxone treatment, suggesting that changes may occur in the endogenous opioid system during aging. In contrast to higher pain thresholds in older animals, however, are decreased concentrations of opiate receptors in the frontal poles, striatum and hippocampus. Anterior cortex and amygdala exhibit a trend toward decreased concentration with increased age, but this is not significant. No age changes in binding affinity occur in any of the brain regions examined. Possible explanations for the apparent discrepancy between altered receptors and response include: higher endogenous opioid levels in aged rats, mediation of pain sensitivity by brain regions other than those examined, difficulties inherent in attempting to localize age changes at a single step in such a complex process, and possibly differential spinal pathways mediating the various types of pain.     

Reuniting overnutrition and undernutrition,macronutrients, and micronutrients

Over‐nutrition and its late consequences are a dominant theme in medicine today. In addition to the health hazards brought on by over‐nutrition, the medical community has recently accumulated a roster of health benefits with obesity, grouped under “obesity paradox.” Throughout the world and throughout history until the 20^th century, under‐nutrition was a dominant evolutionary force. Under‐nutrition brings with it a mix of benefits and detriments that are opposite to and continuous with those of over‐nutrition. This continuum yields J‐shaped or U‐shaped curves relating body mass index to mortality. The overweight have an elevated risk of dying in middle age of degenerative diseases while the underweight are at increased risk of premature death from infectious conditions. Micronutrient deficiencies, major concerns of nutritional science in the 20^th century, are being neglected. This “hidden hunger” is now surprisingly prevalent in all weight groups, even among the overweight. Because micronutrient replacement is safe, inexpensive, and predictably effective, it is now an exceptionally attractive target for therapy across the spectrum of weight and age. Nutrition‐related conditions worthy of special attention from caregivers include excess vitamin A, excess vitamin D, and deficiency of magnesium.