Benefits Of Caloric Restriction Research Articles

Benefits of calorie restriction in mice are mediated via energy imbalance, not absolute energy or protein intake

Caloric restriction (CR) results in reduced energy and protein intake, raising questions about protein restriction’s contribution to CR longevity benefits. We kept ad libitum (AL)–fed male C57BL/6J mice at 27°C (AL27) and pair-fed (PF) mice at 22°C (22(PF27)). The 22(PF27) group was fed to match AL27 while restricted for calories due to cold-induced metabolism. The 22(PF27) mice had significantly lower body weight, lean mass, fat mass, leptin, IGF-1, and TNF-α levels than AL27 mice (p<0.001 for all). Manipulations over ~11 weeks resulted in significant differences in body temperature, physical activity, and expression of key genes linked to hunger in the hypothalamus. Survival was significantly greater in 22(PF27) compared to AL27 overall (p<0.001). CR in the context of equivalent energy and protein intake resulted in hormonal, metabolic, and physiological benefits and extended longevity. Hence, energy imbalance, rather than low energy or protein intake per se, mediates the benefits of CR.

Association of chrononutrition patterns with biological aging: evidence from a nationally representative cross-sectional study.

Previous studies mostly focused on the benefits of caloric restriction and fasting on longevity. However, whether the timing and frequency of eating affect aging remains unclear. Here, we investigated the associations between chrononutrition patterns and biological aging, and explored whether and to what extent dietary inflammation mediated this association. 16 531 adults aged 20 to 84 years from the National Health and Nutrition Examination Survey were collected. Chrononutrition patterns were determined with two 24-hour dietary recalls. Phenotypic age was calculated to reflect the biological aging status. The dietary inflammatory index (DII) was used to assess the dietary inflammation. After adjustment of the survey weight and multiple covariates including total energy intake, participants in the third tertile of the time of the first meal (mean 10 : 26) exhibited more advanced biological age (β 0.64; 95% CI, 0.26-1.00) and a higher incidence of accelerated aging (odds ratio (OR) 1.25; 95% CI, 1.06-1.47) compared to those of the first tertile (mean 6 : 14). Higher eating frequency was associated with delayed biological aging in both multivariable linear (β -0.31; 95% CI, -0.44 to -0.19) and logistic regression model (OR 0.90; 95% CI, 0.85-0.95). Furthermore, we found that DII rather than metabolic factors mediated the inverse association between eating frequency and biological aging (mediation proportion 24.67%; 95% CI, 19.83%-32.00%). Our findings demonstrated the association between chrononutrition patterns and biological aging among the US general population and the potential role of dietary inflammation in this association, suggesting that modifying chrononutrition patterns may be a practical and cost-effective strategy for combating aging.

303-OR: Calorie Restriction Equalizes Glycemic Control between Short and Adequate Sleepers

Many adults receive inadequate sleep, which elevates obesity and type 2 diabetes risk and may hinder benefits of calorie restriction (CR). We hypothesized that short sleepers would experience less weight loss and diminished glycemic benefits compared to adequate sleepers during CR. We performed secondary analyses in participants randomized to 25% CR in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy- Phase 2 (CALERIE 2) trial. Body weight, dual-energy x-ray absorptiometry-measured body composition, fasting glucose, insulin, and HOMA-IR were assessed at baseline, 12, and 24 months. Self-reported sleep duration identified participants with stable sleep as short (≤7 hrs, n=45) or adequate sleepers (&amp;gt;7 hrs, n=65). Sex, BMI, weight, and race-adjusted linear mixed models identified differences over time and between sleepers. Short and adequate sleepers had similar body weight and composition values at all timepoints and experienced equivalent CR-induced reductions over time. Baseline HOMA-IR (1.2 vs. 1.0; P=0.047) was higher in short sleepers, with trends noted for glucose (81.7 vs. 83.5 mg/dL; P=0.093) and insulin (5.7 vs. 4.9 µU/mL; P=0.077). Both phenotypes demonstrated enhanced glycemic control relative to baseline at 12 and 24 months. While there were no 12-month differences in absolute glycemic values between sleepers, initial differences re-emerged at 24 months, with higher HOMA-IR (0.9 vs. 0.7; P=0.01) and insulin concentrations (4.3 vs. 3.4 µU/mL; P&amp;lt;0.01) in short vs. adequate sleepers. Short sleepers had worse baseline glycemic control than adequate sleepers. This difference dissipated during active weight loss but returned during weight maintenance. While short sleepers responded to CR in the present analysis, subsequent work must examine the likely synergy of extending sleep in short sleepers during CR to sustain improvements in glycemic control long-term. Importantly, these data also point to CR as a potential metabolic countermeasure to short sleep. Disclosure K. K. Hoddy: None. P. Singh: None. J. L. Dorling: None. R. A. Beyl: None. J. P. Kirwan: None. K. Huffman: None. S. B. Racette: None. S. Das: None. C. K. Martin: Advisory Panel; Self; EHE Health, Board Member; Self; NaturallySlim, Other Relationship; Self; ABGIL, Academy of Nutrition and Dietetics, Research Support; Self; American Society for Nutrition, Leona M. and Harry B. Helmsley Charitable Trust, Lilly, National Institutes of Health, Patient-Centered Outcomes Research Institute, U. S. Department of Agriculture, WW. Funding National Institute on Aging (U01AG022132, U01AG020478, U01AG020487, U01AG020480, R01AG060499, U24AG047121, U24AG047121); Agricultural Research Service (1950-51000-071-01S); American Heart Association (20POST35210907); National Institute of Diabetes and Digestive and Kidney Diseases (5P30DK07247615); National Institute of General Medical Sciences (U54GM104940)

Short-Term Caloric Restriction Attenuates Obesity-Induced Pro-Inflammatory Response in Male Rhesus Macaques.

White adipose tissue (WAT) hypertrophy is an essential hallmark of obesity and is associated with the activation of resident immune cells. While the benefits of caloric restriction (CR) on health span are generally accepted, its effects on WAT physiology are not well understood. We previously demonstrated that short-term CR reverses obesity in male rhesus macaques exposed to a high-fat Western-style diet (WSD). Here, we analyzed subcutaneous WAT biopsies collected from this cohort of animals before and after WSD and following CR. This analysis showed that WSD induced adipocyte hypertrophy and inhibited β-adrenergic-simulated lipolysis. CR reversed adipocyte hypertrophy, but WAT remained insensitive to β-adrenergic agonist stimulation. Whole-genome transcriptional analysis revealed that β3-adrenergic receptor and de novo lipogenesis genes were downregulated by WSD and remained downregulated after CR. In contrast, WSD-induced pro-inflammatory gene expression was effectively reversed by CR. Furthermore, peripheral blood monocytes isolated during the CR period exhibited a significant reduction in the production of pro-inflammatory cytokines compared to those obtained after WSD. Collectively, this study demonstrates that short-term CR eliminates an obesity-induced pro-inflammatory response in WAT and peripheral monocytes.

Metformin protects red blood cells against rotenone induced oxidative stress and cytotoxicity

Context The anti-diabetic medicine metformin has been reported as an anti-ageing drug candidate as it mimics the benefits of caloric restriction and reduces ageing-related oxidative stress in various experimental organisms. Objective We investigated the possible anti-oxidative role of metformin against rotenone-induced oxidative stress and cytotoxicity in erythrocytes of Wistar rats. Rotenone is a well-known inducer of oxidative stress which leads to a cellular redox imbalance. Materials and methods We have co-exposed the experimental rats with rotenone (2.5 mg/kg, i.p.) and metformin (300 mg/kg, orally) for 30 days to investigate the protective effects of metformin on various rotenone-induced impaired oxidative stress biomarkers in rat erythrocytes. Results We found that a significant alleviation in the levels of rotenone-induced pro-oxidant and anti-oxidant markers following exposure of metformin. Discussion and conclusions Our findings suggest that metformin supplementation shows a protective role in against rotenone-induced redox imbalance and cytotoxicity in rat erythrocytes.

Benefits of Caloric Restriction in Longevity and Chemical-Induced Tumorigenesis Are Transmitted Independent of NQO1.

Caloric restriction (CR) is the most potent nonpharmacological intervention known to both protect against carcinogenesis and delay aging in laboratory animals. There is a growing number of anticarcinogens and CR mimetics that activate NAD(P)H:quinone oxidoreductase 1 (NQO1). We have previously shown that NQO1, an antioxidant enzyme that acts as an energy sensor through modulation of intracellular redox and metabolic state, is upregulated by CR. Here, we used NQO1-knockout (KO) mice to investigate the role of NQO1 in both the aging process and tumor susceptibility, specifically in the context of CR. We found that NQO1 is not essential for the beneficial effects of CR on glucose homeostasis, physical performance, metabolic flexibility, life-span extension, and (unlike our previously observation with Nrf2) chemical-induced tumorigenesis.

Effects of Calorie Restriction in Obese Older Adults: The CROSSROADS Randomized Controlled Trial.

We lack a comprehensive assessment of the risks and benefits of calorie restriction in older adults at high risk for cardiometabolic disease. Calorie restriction may reduce visceral adipose tissue (VAT) but also have negative effects on lean mass and quality of life. We conducted a 52-week, randomized controlled trial involving 164 older adults with obesity taking at least one medication for hyperlipidemia, hypertension, or diabetes. Interventions included an exercise intervention alone (Exercise), or with diet modification and body weight maintenance (Maintenance), or with diet modification and energy restriction (Weight Loss). The primary outcome was change in VAT at 12 months. Secondary outcomes included cardiometabolic risk factors, functional status, and quality of life. A total of 148 participants had measured weight at 12 months. Despite loss of -1.6% ± 0.3% body fat and 4.1% ± 0.7% initial body weight, Weight Loss did not have statistically greater loss of VAT (-192.6 ± 185.2 cm3) or lean mass (-0.4 ± 0.3 kg) compared with Exercise (VAT = -21.9 ± 173.7 cm3; lean mass = 0.3 ± 0.3 kg). Quality of life improved in all groups with no differences between groups. No significant changes in physical function were observed. Weight Loss had significantly greater improvements in blood glucose (-8.3 ± 3.6 mg/dL, p < .05) and HDL-cholesterol (5.3 ± 1.9, p < .01) compared with Exercise. There were no group differences in the frequency of adverse events. While moderate calorie restriction did not significantly decrease VAT in older adults at high risk for cardiometabolic disease, it did reduce total body fat and cardiometabolic risk factors without significantly more adverse events and lean mass loss.

Benefits of caloric restriction in the myenteric neuronal plasticity in aging rats.

Aging is a biologic process characterized by progressive damage of structures and functions of organic systems. In gastrointestinal tract, it can involve enteric nervous system, which plays an important role in digestion and absorption of nutrients, causing hastening of intestinal transit thus reducing its absorptive function. Caloric restriction has been used in several studies with the intention of delaying deleterious effects of aging. This study aimed to evaluate the effects of caloric restriction on myenteric neurons of ileum by aging in rats. 30 Wistar rats were grouped as follows: GI (animals aged 6 months fed with normal diet), GII (animals aged 18 months fed with normal diet) and GIII (animals aged 18 months subject to 31% of caloric restriction). The rats of the GI group were euthanized at 6 months of age and after experimental period of 12 months animals of the group GII and GIII were euthanized, the ileum of all groups were collected, measured and processed by NADPH-dp and Acetylcholinesterase. Quantitative analysis of neurons revealed that aging promotes the increasing of myenteric neurons NADPH-dp and reduces Acetylcholinesterase neuronal population. However, in the cellular profile area, were not observed significant differences between the groups. The caloric restriction has been efficient and can be used preventively because it minimizes quantitative changes associated with aging on ileum myenteric plexuses.

137. Acute calorie restriction as a modulator of anxiety-like behavior

Neurological disorders, such as depression, cognitive decline, and anxiety, are a growing class of chronic diseases. Recently, several studies have highlighted the role of inflammation in the pathogenesis of these disorders, specifically caspase-1 mediated activation of IL-1β. Additionally, acute calorie restriction has been shown to have anti-inflammatory effects, and improve sickness behaviors. While the benefits of calorie restriction are well known, the specific mechanism by which it modulates behavior is yet to be determined. In the current study mice were subjected to acute calorie restriction in the form of a 24 h fast to determine how calorie restriction can modulate anxiety-like behavior. Fasted mice displayed reduced anxiety-like behavior as measured by an elevated zero maze, while exhibiting no changes in locomotor activity during the task. Additionally, fasted mice exhibited reduced brain caspase-1 activity and a parallel reduction in IL-1β gene expression in the whole brain, amygdala, and hypothalamus. Taken together our data suggest that acute calorie restriction can improve anxiety-like behavior through a reduction in brain caspase-1 activity and IL-1 gene expression in specific brain regions.

Carboxamide SIRT1 inhibitors block DBC1 binding via an acetylation-independent mechanism

SIRT1 is an NAD+-dependent deacetylase that counteracts multiple disease states associated with aging and may underlie some of the health benefits of calorie restriction. Understanding how SIRT1 is regulated in vivo could therefore lead to new strategies to treat age-related diseases. SIRT1 forms a stable complex with DBC1, an endogenous inhibitor. Little is known regarding the biochemical nature of SIRT1-DBC1 complex formation, how it is regulated and whether or not it is possible to block this interaction pharmacologically. In this study, we show that critical residues within the catalytic core of SIRT1 mediate binding to DBC1 via its N-terminal region, and that several carboxamide SIRT1 inhibitors, including EX-527, can completely block this interaction. We identify two acetylation sites on DBC1 that regulate its ability to bind SIRT1 and suppress its activity. Furthermore, we show that DBC1 itself is a substrate for SIRT1. Surprisingly, the effect of EX-527 on SIRT1-DBC1 binding is independent of DBC1 acetylation. Together, these data show that protein acetylation serves as an endogenous regulatory mechanism for SIRT1-DBC1 binding and illuminate a new path to developing small-molecule modulators of SIRT1.

Caloric restriction and its mimetics

Caloric restriction is the most reliable intervention to prevent age-related disorders and extend lifespan. The reduction of calories by 10-30% compared to an ad libitum diet is known to extend the longevity of various species from yeast to rodents. The underlying mechanisms by which the benefits of caloric restriction occur have not yet been clearly defined. However, many studies are being conducted in an attempt to elucidate these mechanisms, and there are indications that the benefits of caloric restriction are related to alteration of the metabolic rate and the accumulation of reactive oxygen species. During molecular signaling, insulin/insulin-like growth factor signaling, target of rapamycin pathway, adenosine monophosphate activated protein kinase signaling, and Sirtuin are focused as underlying pathways that mediate the benefits of caloric restriction. Here, we will review the current status of caloric restriction. [BMB Reports 2013; 46(4): 181-187]

Resveratrol Supplementation Does Not Improve Metabolic Function in Nonobese Women with Normal Glucose Tolerance

Resveratrol has been reported to improve metabolic function in metabolically abnormal rodents and humans, but it has not been studied in nonobese people with normal glucose tolerance. We conducted a randomized, double-blind, placebo-controlled trial to evaluate the metabolic effects of 12weeks of resveratrol supplementation (75mg/day) in nonobese, postmenopausal women with normal glucosetolerance. Although resveratrol supplementation increased plasma resveratrol concentration, it did not change body composition, resting metabolic rate, plasma lipids, or inflammatory markers. A two-stage hyperinsulinemic-euglycemic clamp procedure, in conjunction with stable isotopically labeled tracer infusions, demonstrated that resveratrol did not increase liver, skeletal muscle, or adipose tissue insulin sensitivity. Consistent with the absence of invivo metabolic effects, resveratrol did not affect its putative molecular targets, including AMPK, SIRT1, NAMPT, and PPARGC1A, in either skeletal muscle or adipose tissue. These findings demonstrate that resveratrol supplementation does not have beneficial metabolic effects innonobese, postmenopausal women with normal glucose tolerance.

Using PDE inhibitors to harness the benefits of calorie restriction: lessons from resveratrol

In conclusion, the discovery of the resveratrol-PDE link suggests that PDE4 inhibitors, possibly in combination with other PDE inhibitors, may be useful for mimicking CR and for treating aging-related diseases.

Abstract 2075: miRs are altered by caloric restriction: Therapeutic implications

Abstract The anti-cancer effect of caloric restriction (CR) is thought to involve repression of insulin/IGF-1 signaling, which activates PI3k/AKT, a pro-proliferation pathway that is often up regulated in tumor cells. Several microRNAs have been shown to play roles in tumor suppression and oncogenesis. In this study we sought to determine what if any microRNAs can play a role in the anticancer effects of caloric restriction. To determine this we performed microRNA arrays on total RNA from ad libitum fed, CR, or 24-hour fasted C57b/J mice. We assessed liver and brain tissues since these are known to have great alterations with caloric restriction and we also assessed breast tissue for which there is little data with dietary alteration. Our results show that both caloric restriction and fasting alters the expression of several cancer relevant microRNAs all of the tissues analyzed. A reduction of the miR-200 and mir-17-92 cluster of miRNAs was noted and these miR's are known to be upregulated in many cancers. Conversely, increases in the mir-29 and mir-30 families of miRNAs were noted which are noted to be downregulated in many cancers. mir-29 is known to target p85 protein of PI3K which would also reduce AKT signaling. In addition, mir-29 and mir-30 are predicted to target IGF-1 and IGF-1R respectively. Analyses of protein and mRNA levels confirm that IGF-1 and IGF-1 R are down regulated by CR and fasting. Cell culture studies are ongoing to show direct targeting of these transcripts by mir-29 and mir-30. This study shows that microRNAs are involved in the potential benefits of caloric restriction and show a general role for regulation of insulin related signaling by mir-29 and mir-30 which may be provide a target that can be exploited for therapeutic benefit. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2075. doi:10.1158/1538-7445.AM2011-2075

Moderate Caloric Restriction Suppresses microRNAs miR-696 and miR-199a in a Voluntary Running Wheel Model

The transcriptional coactivator PGC-1α is central to skeletal muscle adaptation to increased physical activity. SIRT1, an energy sensing deacetylase, and important regulator of transcription, plays a role in the benefits of caloric restriction. SIRT1 is also a regulator of PGC-1αin skeletal muscle. MicroRNAs (miRNAs) are short noncoding RNA molecules involved in post-transcriptional regulation of gene expression by binding to target mRNA. Expression levels of miRNAs can be altered by physiological stimuli. miR-696 and miR-199a are reported to target PGC-1αand SIRT1, respectively. Neither expression of miR-696 nor miR-199a has been studied in the adaptation of skeletal muscle to physical activity and moderate caloric restriction (CR). PURPOSE: We tested the hypothesis that moderate CR in physically active mice would suppress expression of miR-696 and miR-199a. METHODS: Male C57BL/6J mice (9 wks old) were individually housed and assigned to one of two groups: ad libitum feeding (AL, n=7) or moderate CR (n=6). The AL mice had free access to food and a running wheel for 23 days. The moderate CR mice had free access to a running wheel for 23 days and free access to food for the initial 8 days, and then moderate CR for 15 days. The moderate CR protocol was implemented to achieve a 20% reduction in body mass within 3 days. Body mass reduction was then maintained for the remainder of the experiment. Running distance was measured daily. Total RNA was isolated from the plantaris (PLA). Total RNA and microRNA were reverse transcribed in separate reactions to measure expression levels of COXI, PGC-1α, and SIRT1, or miR-696, miR-199a. The relative copy number of mitochondrial (mt) DNA was measured in total DNA (nuclear and mitochondrial) extracted from PLA. RESULTS: The moderate CR group required a 26% decrease in food intake to achieve the 20% decrease in body mass. During the 15 days of moderate CR mice ran 10.5 km/day while the AL mice ran 6.9 km/day (p<0.05). mtDNA copy number and COXI expression were significantly (p<0.05) greater, 27% and 64% respectively, in moderate CR mice, while PGC-1αexpression was not affected (p>0.05). However, miR-696 expression was suppressed (70%, p<0.05) in moderate CR mice. Moderate CR resulted in increased SIRT1 expression (66%, p<0.05) and conversely, decreased miR-199a expression (58%, p<0.05). CONCLUSION: Compared to wheel running alone, moderate CR significantly increased running wheel distance, COX1 and SIRT1 mRNA expression, mtDNA copy number, and suppresses microRNAs miR-696 and miR-199a in physically active mice. These data suggest that moderate CR may regulate mitochondrial biogenesis through post-transcriptional mechanisms.

The hydrogen sulfide signaling system: changes during aging and the benefits of caloric restriction

Hydrogen sulfide gas (H(2)S) is a putative signaling molecule that causes diverse effects in mammalian tissues including relaxation of blood vessels and regulation of perfusion in the liver, but the effects of aging on H(2)S signaling are unknown. Aging has negative impacts on the cardiovascular system. However, the liver is more resilient with age. Caloric restriction (CR) attenuates affects of age in many tissues. We hypothesized that the H(2)S signaling system is negatively affected by age in the vasculature but not in the liver, which is typically more resilient to age, and that a CR diet minimizes the age affect in the vasculature. To investigate this, we determined protein and mRNA expression of the H(2)S-producing enzymes cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS), H(2)S production rates in the aorta and liver, and the contractile response of aortic rings to exogenous H(2)S. Tissue was collected from Fisher 344 × Brown Norway rats from 8-38 months of age, which had been maintained on an ad libitum (AL) or CR diet. The results demonstrate that age and diet have differential effects on the H(2)S signaling system in aorta and liver. The aorta showed a sizeable effect of both age and diet, whereas the liver only showed a sizeable effect of diet. Aortic rings showed increased contractile sensitivity to H(2)S and increased protein expression of CSE and CBS with age, consistent with a decrease in H(2)S concentration with age. CR appears to benefit CSE and CBS protein in both aorta and liver, potentially by reducing oxidative stress and ameliorating the negative effect of age on H(2)S concentration. Therefore, CR may help maintain the H(2)S signaling system during aging.

The Benefits of Calorie Restriction and Calorie Restriction Mimetics as Related to the Eye

The effects of calorie restriction without malnutrition seem to possess many beneficial effects in numerous disease states. Recently, studies related to calorie restriction mimetics that biochemically mimic the effects of calorie restriction are also becoming increasingly popular. Both calorie restriction and calorie restriction mimetics trigger an adaptive response reminiscent of mild-stress or low-dose toxic response, which is frequently referred to as hormesis in the toxicology literature. Although some benefits of calorie restriction and calorie restriction mimetics have been studied, the role of hormesis-related pathways in the eye has not been given a special attention. This review will present the current literature on calorie restriction and calorie restriction mimetics as related to most prominent eye diseases and provide insights on the therapeutic role of hormesis in eye diseases.

The Benefits of Calorie Restriction and Calorie Restriction Mimetics as Related to the Eye

The Benefits of Calorie Restriction and Calorie Restriction Mimetics as Related to the Eye

Benefits of Caloric Restriction on Brain Aging and Related Pathological States: Understanding Mechanisms to Devise Novel Therapies

Long term caloric restriction is known to counteract aging and extend lifespan in several organisms from yeasts to mammals. Recent research has provided solid ground to the concept that limiting calorie intake slows down brain aging and protects from age-related neurodegenerative diseases. The present review summarizes the most relevant among these data and highlights some genetic and molecular mechanisms responsible for caloric restriction-related neuroprotection. To understand these mechanisms is important because this information makes them potential targets for therapeutic intervention aimed at reproducing the metabolic, genetic and molecular features responsible for the beneficial effect of caloric restriction. Most promising among these targets are neurotrophins, such as BDNF, transcription factors, such as FoxO and PPAR, anti-aging proteins, such as sirtuins, and caloric restriction mimetics acting on oxidative stress and energy metabolism. Notwithstanding the complexity of any therapeutic strategy aimed at reproducing the beneficial effects of caloric restriction, due to multiplicity of the cellular pathways involved in the responses, a great expansion of medicinal chemistry research in this field is expected in the next future.

An Age-Old Problem

R apid advances in the basic and medical sciences, while rapidly expanding our knowledge base on a host of physiological processes (and their cellular and organismal consequences when disrupted), are also posing a significant burden. The sheer volume of information amassed from a host of experimental systems and model organisms can represent a daunting assimilation task to both the neophyte and the experienced investigator, a problem often compounded by contradictory and/or conflicting data that are inherent to the constant flux of scientific discovery. With these challenges in mind, we are pleased to introduce a new series initiative by PLoS Genetics. In keeping with the mission statement of our journal to present interdisciplinary research in the broadest possible context, we have commissioned a series of Review and Opinion articles bound thematically to a discrete set of topics of inherent complexity, as well as broad interest. Each component of the series will examine a facet of the chosen problem and we hope that the amalgam of each series, which will be available electronically as a unified entity, will both educate the non-specialist as well as provide a balanced view that will transmit to our readership an appreciation of the progress made and the future trends in each field. Our inaugural series focuses on aging, a field under both rapid evolution and substantial controversy. Humans are arguably unique among sentient species in that we are cognizant of our own mortality even at moments when it is not imminent—a fact that has constituted a major force in shaping our civilization (in all its iterations). The advent of molecular biology and genetics has offered a unique opportunity to help us understand why organisms age, which in turn might offer clues as to how one might decelerate, stop, or even reverse this process. When examining the field of aging research, we can identify three major spheres: cellular aging (senescence/quiescence), organismal aging, and age-related disorders. In this series, we will focus primarily of the first two areas, because the study of age-related disorders does not necessarily inform the basic questions, namely: (a) what are the basic determinants of lifespan, and (b) what are the fundamental cellular and molecular mechanisms that underscore aging processes? Like most disciplines, aging research has benefited from the availability of a host of prokaryotic and eukaryotic model organisms. However, although some aging mechanisms seem to hold true in diverse species, such as the benefits of caloric restriction in prolonging lifespan, there are also multiple aging mechanisms, and their possible clade specificity has generated potential for controversy. This highlights an important feature of the aging process; aging occurs in many species in nature, and is particularly obvious in captivity where natural hazard is removed. The aging process is in itself, however, nonadaptive and it evolves because natural selection is relatively powerless to act on the traits of older individuals. Nonetheless, the study of both species-specific and ubiquitous aging mechanisms will inform the biological process of aging and will ultimately be better reflected in the management of aging in humans. We are pleased to introduce the first element of our series in this month’s issue, in which Tom Prolla and colleagues will discuss the effect of doi:10.1371/journal.pgen.0030037.g001