Review of the literature and suggestions for the design of rodent survival studies for the identification of compounds that increase health and life span

Much of the literature describing the search for agents that increase the life span of rodents was found to suffer from confounds. One-hundred-six studies, absent 20 contradictory melatonin studies, of compounds or combinations of compounds were reviewed. Only six studies reported both life span extension and food consumption data, thereby excluding the potential effects of caloric restriction. Six other studies reported life span extension without a change in body weight. However, weight can be an unreliable surrogate measure of caloric consumption. Twenty studies reported that food consumption or weight was unchanged, but it was unclear whether these data were anecdotal or systematic. Twenty-nine reported extended life span likely due to induced caloric restriction. Thirty-six studies reported no effect on life span, and three a decrease. The remaining studies suffer from more serious confounds. Though still widely cited, studies showing life span extension using short-lived or “enfeebled” rodents have not been shown to predict longevity effects in long-lived animals. We suggest improvements in experimental design that will enhance the reliability of the rodent life span literature. First, animals should receive measured quantities of food and its consumption monitored, preferably daily, and reported. Weights should be measured regularly and reported. Second, a genetically heterogeneous, long-lived rodent should be utilized. Third, chemically defined diets should be used. Fourth, a positive control (e.g., a calorically restricted group) is highly desirable. Fifth, drug dosages should be chosen based on surrogate endpoints or accepted cross-species scaling factors. These procedures should improve the reliability of the scientific literature and accelerate the identification of longevity and health span-enhancing agents

Impact of caloric and dietary restriction regimens on markers of health and longevity in humans and animals: a summary of available findings

Considerable interest has been shown in the ability of caloric restriction (CR) to improve multiple parameters of health and to extend lifespan. CR is the reduction of caloric intake - typically by 20 - 40% of ad libitum consumption - while maintaining adequate nutrient intake. Several alternatives to CR exist. CR combined with exercise (CE) consists of both decreased caloric intake and increased caloric expenditure. Alternate-day fasting (ADF) consists of two interchanging days; one day, subjects may consume food ad libitum (sometimes equaling twice the normal intake); on the other day, food is reduced or withheld altogether. Dietary restriction (DR) - restriction of one or more components of intake (typically macronutrients) with minimal to no reduction in total caloric intake - is another alternative to CR. Many religions incorporate one or more forms of food restriction. The following religious fasting periods are featured in this review: 1) Islamic Ramadan; 2) the three principal fasting periods of Greek Orthodox Christianity (Nativity, Lent, and the Assumption); and 3) the Biblical-based Daniel Fast. This review provides a summary of the current state of knowledge related to CR and DR. A specific section is provided that illustrates related work pertaining to religious forms of food restriction. Where available, studies involving both humans and animals are presented. The review includes suggestions for future research pertaining to the topics of discussion

Brain volumetric and microstructural correlates of executive and motor performance in aged rhesus monkeys

The aged rhesus macaque exhibits brain atrophy and behavioral deficits similar to normal aging in humans. Here we studied the association between cognitive and motor performance and anatomic and microstructural brain integrity measured with 3T magnetic resonance imaging in aged monkeys. About half of these animals were maintained on moderate calorie restriction, the only intervention shown to delay the aging process in lower animals. T1-weighted anatomic and diffusion tensor images were used to obtain gray matter volume, and fractional anisotropy and mean diffusivity, respectively. We tested the extent to which brain health indexed by gray matter volume, fractional anisotropy, and mean diffusivity were related to executive and motor function, and determined the effect of the dietary intervention on this relationship. We hypothesized that fewer errors on the executive function test and faster motor times would be correlated with higher volume, higher fractional anisotropy, and lower mean diffusivity in frontal areas that mediate executive function, and in motor, premotor, subcortical, and cerebellar areas underlying goal-directed motor behaviors. Higher error percentage on a cognitive conceptual shift task was significantly associated with lower gray matter volume in frontal and parietal cortices, and lower fractional anisotropy in major association fiber bundles. Similarly, slower performance time on the motor task was significantly correlated with lower volumetric measures in cortical, subcortical, and cerebellar areas and decreased fractional anisotropy in several major association fiber bundles. Notably, performance during the acquisition phase of the hardest level of the motor task was significantly associated with anterior mesial temporal lobe volume. Finally, these brain-behavior correlations for the motor task were attenuated in calorie restricted animals compared to controls, indicating a potential protective effect of the dietary intervention

SIRT1 regulates PGC-1α subcellular localization and activity in response to stress

<p><b>Copyright information:</b></p><p>Taken from "Dynamic regulation of PGC-1α localization and turnover implicates mitochondrial adaptation in calorie restriction and the stress response"</p><p></p><p>Aging Cell 2008;7(1):101-111.</p><p>Published online Jan 2008</p><p>PMCID:PMC2253697.</p><p>© 2008 The Authors Journal compilation © Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 2008</p> (A) Percent survival of cells after exposure to HO (350 µ, 1 h) with or without nicotinamide (10 m); values represent means ± standard error of the mean; * indicates significant difference in survival compared to control cells; + indicates significant difference in survival compared to peroxide-treated control cells ( < 0.05). (B) Immunofluorescent detection of PGC-1α and SIRT1 in cells following treatment with HO (350 µ). Nuclei were visualized with DAPI stain. (C) PGC-1α in cytoplasmic (cyt) and nuclear (nuc) subcellular fractions in cultured cells after treatment with HO (350 µ, 45 min), with or without nicotinamide (10 m). (D) Immunofluorescent detection of PGC-1α in nicotinamide-treated cells (10 m) after treatment with hydrogen peroxide (350 µ, 45 min). (E) Mitotracker Red detection of mitochondrial membrane potential after exposure to HO (350 µ, 1 h) in nicotinamide- (10 m) treated cells. (F) Detection of acetylated PGC-1α by Western in immunoprecipitates from cells following exposure to hydrogen peroxide (350 m), with and without nicotinamide (10 m)

GSK3β-dependent phosphorylation of peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α) in reponse to stress

<p><b>Copyright information:</b></p><p>Taken from "Dynamic regulation of PGC-1α localization and turnover implicates mitochondrial adaptation in calorie restriction and the stress response"</p><p></p><p>Aging Cell 2008;7(1):101-111.</p><p>Published online Jan 2008</p><p>PMCID:PMC2253697.</p><p>© 2008 The Authors Journal compilation © Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 2008</p> (A) Immunofluorescent detection of PGC-1α in cells 24 h following siRNA with negative control or GSK3β-specific oligonucleotides. Knock down of GSK3β detected by Western blot (lower panel). (B) Western blot detection of PGC-1α in extracts taken at the indicated times in minutes following hydrogen peroxide treatment (350 µ); cells were grown under normal conditions or in the presence of GSK3β inhibitor VII (20 µ) prior to and during stress. (C) Detection of PGC-1α by Western blot of GSK3β immunoprecipitates from untreated or hydrogen-peroxide-treated cells (350 µ, 15 min); cells were grown in the absence or presence of GSK3β inhibitor VII (20 µ). (D) Detection of PGC-1α in phosphoserine and phosphothreonine immunoprecipitates from hydrogen-peroxide-treated cells (350 µ, 15 min); cells were grown in the absence or presence of GSK3β inhibitor VII (20 µ). (E) Detection of phosphoserine and phosphothreonine phosphorylated species by Western blot of PGC-1α immunoprecipitates from hydrogen-peroxide-treated cells (350 µ, 15 min); cells were grown in the absence or presence of GSK3β inhibitor VII (20 µ). (F) Model of PGC-1α activation in response to oxidative stress

PGC-1α is regulated by SIRT1 and GSK3β during oxidative stress and calorie restriction (CR) in mice

<p><b>Copyright information:</b></p><p>Taken from "Dynamic regulation of PGC-1α localization and turnover implicates mitochondrial adaptation in calorie restriction and the stress response"</p><p></p><p>Aging Cell 2008;7(1):101-111.</p><p>Published online Jan 2008</p><p>PMCID:PMC2253697.</p><p>© 2008 The Authors Journal compilation © Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 2008</p> (A) Western detection of PGC-1α in nuclear (nuc) and cytoplasmic (cyt) subcellular fractions from skeletal muscle of 5-month-old mice taken at indicated hours following exposure to paraquat (50 mg kg body weight). Densitometric analysis of normalized PGC-1α levels detected in cytoplasmic and nuclear fractions at indicated times. (B) Western detection of SIRT1, GSK3β and phospho-GSK3β in whole tissue homogenates of skeletal muscle of 5-month-old mice taken at indicated hours following exposure to paraquat (50 mg kg body weight). (C) Western detection of UCP3 and COX IV in cytoplasmic fraction of skeletal muscle of 5-month-old mice taken at indicated hours following exposure to paraquat (50 mg kg body weight). (D) Western detection of SIRT1, phospho-c-Jun N-terminal kinase (JNK), JNK, phospho-GSK3β and GSK3β in white adipose tissue from control (Control) and restricted (CR) 10-month-old mice. (E) Model describing regulation of PGC-1α that permits transient or sustained effects on PGC-1α activity