Abstract The calorie restriction paradigm has provided one of the most widely used and most useful tools for investigating mechanisms of aging and longevity. By far, rodent models have been employed ...most often in these endeavors. Over decades of investigation, claims have been made that the paradigm produces the most robust demonstration that aging is malleable. In the current review of the rodent literature, we present arguments that question the robustness of the paradigm to increase lifespan and healthspan. Specifically, there are several questions to consider as follows: (1) At what age does CR no longer produce benefits? (2) Does CR attenuate cognitive decline? (3) Are there negative effects of CR, including effects on bone health, wound healing, and response to infection? (4) How important is schedule of feeding? (5) How long does CR need to be imposed to be effective? (6) How do genotype and gender influence CR? (7) What role does dietary composition play? Consideration of these questions produce many caveats that should guide future investigations to move the field forward.
Caloric restriction (CR) without malnutrition extends lifespan and delays the onset of age-related disorders in most species but its impact in nonhuman primates has been controversial. In the late ...1980s two parallel studies were initiated to determine the effect of CR in rhesus monkeys. The University of Wisconsin study reported a significant positive impact of CR on survival, but the National Institute on Aging study detected no significant survival effect. Here we present a direct comparison of longitudinal data from both studies including survival, bodyweight, food intake, fasting glucose levels and age-related morbidity. We describe differences in study design that could contribute to differences in outcomes, and we report species specificity in the impact of CR in terms of optimal onset and diet. Taken together these data confirm that health benefits of CR are conserved in monkeys and suggest that CR mechanisms are likely translatable to human health.
Despite a wealth of clinical data showing an association between inflammation and degenerative disorders in the elderly, the immune sensors that causally link systemic inflammation to aging remain ...unclear. Here we detail a mechanism by which the Nlrp3 inflammasome controls systemic low-grade age-related “sterile” inflammation in both periphery and brain independently of the noncanonical caspase-11 inflammasome. Ablation of Nlrp3 inflammasome protected mice from age-related increases in the innate immune activation, alterations in CNS transcriptome, and astrogliosis. Consistent with the hypothesis that systemic low-grade inflammation promotes age-related degenerative changes, the deficient Nlrp3 inflammasome-mediated caspase-1 activity improved glycemic control and attenuated bone loss and thymic demise. Notably, IL-1 mediated only Nlrp3 inflammasome-dependent improvement in cognitive function and motor performance in aged mice. These studies reveal Nlrp3 inflammasome as an upstream target that controls age-related inflammation and offer an innovative therapeutic strategy to lower Nlrp3 activity to delay multiple age-related chronic diseases.
Display omitted
•Age-related DAMPs activate canonical Nlrp3 inflammasome without engaging caspase-11•Reduction in the Nlrp3 inflammasome activity reduces age-related inflammation•Ablation of Nlrp3 inflammasome slows age-related degenerative changes•IL-1 partakes in regulating age-related CNS inflammation and functional decline
Objectives: The aim of this review was to provide an overview of studies conducted to determine the effects of chlorogenic acid (CGA) on cognition and neurological health.
Methods: A literature ...search was conducted using PubMed and various search terms including chlorogenic acid, CGA, memory, neuroscience, cognition, nutrition, antioxidant, pharmacokinetics, neuroprotection, and neurodegeneration.
Results: Many studies have linked CGA consumption to a wide range of health benefits, including neuroprotection, cardioprotection, weight loss, chemopreventive properties, anti-inflammatory activity, decreased blood pressure, decreased diet-induced insulin resistance, decreased blood pressure, anxiolytic effects, and antihyperalgesic effects. Pre-clinical and clinical studies both provide evidence that CGA supplementation could protect against neurological degeneration and the resulting diseases associated with oxidative stress in the brain; however, no formal, well-controlled studies have been performed to date.
Discussion: Recent research suggests that dietary consumption of CGA could produce a wide range of health benefits and physiological effects. There is also mounting evidence that the consumption of polyphenols, including CGA, in the diet could reduce the risk of developing neurodegenerative conditions. Further studies should be conducted with a focus on the effects of CGA on cognition and the nervous system and employing well-designed clinical studies.
The importance of dietary composition and feeding patterns in aging remains largely unexplored, but was implicated recently in two prominent nonhuman primate studies. Here, we directly compare in ...mice the two diets used in the primate studies focusing on three paradigms: ad libitum (AL), 30% calorie restriction (CR), and single-meal feeding (MF), which accounts for differences in energy density and caloric intake consumed by the AL mice. MF and CR regimes enhanced longevity regardless of diet composition, which alone had no significant impact within feeding regimens. Like CR animals, MF mice ate quickly, imposing periods of extended daily fasting on themselves that produced significant improvements in morbidity and mortality compared with AL. These health and survival benefits conferred by periods of extended daily fasting, independent of dietary composition, have major implications for human health and clinical applicability.
Display omitted
•The duration of eating/fasting varies based on diet type and feeding protocol•Meal feeding and CR, unlike AL, show high metabolic flexibility in male mice•Eating patterns rather than diet composition influence longevity regulation•A prolonged daily fasting is associated with delayed onset of liver pathologies
Mitchell et al. show that a long daily period of fasting improves the health and survival of male mice, regardless of caloric intake, diet composition, and body weight.
Calorie restriction (CR), a reduction of 10–40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and healthspan. CR is frequently used as ...a tool to understand mechanisms behind ageing and age-associated diseases. In addition to and independently of increasing lifespan, CR has been reported to delay or prevent the occurrence of many chronic diseases in a variety of animals. Beneficial effects of CR on outcomes such as immune function, motor coordination and resistance to sarcopenia in rhesus monkeys have recently been reported. We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. Our findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7–14 years) and a preliminary report with a small number of CR monkeys. Over the years, both NIA and WNPRC have extensively documented beneficial health effects of CR in these two apparently parallel studies. The implications of the WNPRC findings were important as they extended CR findings beyond the laboratory rodent and to a long-lived primate. Our study suggests a separation between health effects, morbidity and mortality, and similar to what has been shown in rodents, study design, husbandry and diet composition may strongly affect the life-prolonging effect of CR in a long-lived nonhuman primate.
Summary
The workshop entitled ‘Interventions to Slow Aging in Humans: Are We Ready?’ was held in Erice, Italy, on October 8–13, 2013, to bring together leading experts in the biology and genetics of ...aging and obtain a consensus related to the discovery and development of safe interventions to slow aging and increase healthy lifespan in humans. There was consensus that there is sufficient evidence that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age. Essential pathways have been identified, and behavioral, dietary, and pharmacologic approaches have emerged. Although many gene targets and drugs were discussed and there was not complete consensus about all interventions, the participants selected a subset of the most promising strategies that could be tested in humans for their effects on healthspan. These were: (i) dietary interventions mimicking chronic dietary restriction (periodic fasting mimicking diets, protein restriction, etc.); (ii) drugs that inhibit the growth hormone/IGF‐I axis; (iii) drugs that inhibit the mTOR–S6K pathway; or (iv) drugs that activate AMPK or specific sirtuins. These choices were based in part on consistent evidence for the pro‐longevity effects and ability of these interventions to prevent or delay multiple age‐related diseases and improve healthspan in simple model organisms and rodents and their potential to be safe and effective in extending human healthspan. The authors of this manuscript were speakers and discussants invited to the workshop. The following summary highlights the major points addressed and the conclusions of the meeting.
Highlights • We review the literature pertaining to calorie restriction mimetics (CRM). • We discuss history, definitions, and applications of CRM. • We discuss the concept of upstream and downstream ...targeting. • We review the leading candidates for developing CRM. • We suggest where the field is heading.
PDF
