Beyond weight loss: current perspectives on the impact of calorie restriction on healthspan and lifespan

Abstract

Introduction:

Changes to mental, physical, and physiological functions drive the complex processes underlying the variable progression of human aging. Nutritional interventions are one of the most promising non-pharmacological therapeutics to attenuate aging in humans. This narrative review aims to describe the implications of moderate and prolonged calorie restriction (CR) in healthy adults without obesity that occur beyond weight loss.

Areas covered:

Findings from CR studies, such as the CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) trials, the most rigorous trials to date examining a prolonged 25% CR, are described. The main areas covered include; changes to anthropometrics, energy metabolism, cardiometabolic health, inflammation and immune function, physical fitness, health behaviors, and mental health in response to weight loss (1-year) and weight loss maintenance (2-year).

Expert opinion:

CR presents a novel and effective therapeutic approach for improving healthspan and biomarkers of lifespan. To date, scientific evidence suggests that continued CR, under medical supervision, is accompanied with persistent and beneficial effects on health outcomes independent of weight loss. Mechanisms are yet to be fully elucidated, and novel dietary approaches that may similarly attenuate aging-related conditions should be explored and compared to traditional CR.

1. Introduction

1.1. Healthy aging

Human aging is a complex and multifactorial process that results in declines to mental, physical, and physiological functions. While chronological age advances at the same rate in all individuals, biological age, or the gradual and progressive decline in physiological systems, remains highly variable. Biological age is influenced by extrinsic factors, including health behaviors and the environment. Biological age may determine lifespan and healthspan, the length of life free from chronic disease [1]. With advances to medical care, individuals are now able to live with chronic disease over a longer lifespan [2]. Thereby, as the world’s population grows older, countries, societies, and individuals face increased economic burdens to manage chronic disease and its associated disabilities [3].

Nutritional interventions are one of the most promising non-pharmacological therapeutics to attenuate human aging and disease. Currently, a reduction in caloric intake while maintaining optimal nutrition, termed calorie restriction (CR), is the most effective lifestyle intervention to prolong healthspan, slow biological aging, and improve quality of life [4,5]. Indeed, the world’s longest-lived population, Okinawans, have been shown to consume nutrient rich diets with fewer calories [6]. For almost a century, studies in numerous animal species including yeast, flies, and rodents have shown that sustained CR extends lifespan by 50–300% [7]. These preclinical models have suggested that CR extends lifespan through a series of physiological mechanisms, including reduced rate of metabolic activity, oxidative stress, autophagy, and inflammation [1].

Built upon the robust evidence of lifespan extension in preclinical research, the largest and most advanced clinical trials measuring the effects of CR on human aging were initiated by the National Institute of Aging in 2002. These trials are known as the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trials. CALERIE 1 encompassed three independent pilot trials to test various levels (20%, 25%, 30%) and formats (combination of diet and exercise, varying glycemic loads) of CR over six to twelve months in adults and the elderly [8–10]. The results of these pilot trials informed the largest CR multi-site trial to date. CALERIE 2 tested a 25% CR intervention to examine the effects of CR in young adults (n = 220) without obesity over the course of two years. Together, these rigorous trials provide support for the beneficial effects of CR on aging in humans.

1.2. Prescription and support of a CR diet

Using data from the CALERIE trials, estimates of daily energy requirements, or total daily energy expenditure (TDEE)–which can be used to prescribe a 25% CR (i.e. 75% of weight maintenance energy requirements) for adults without obesity–were established [11]. Energy requirements can be computed from a simple measure of body weight or more accurately utilizing body compositions (Box).

Box. Equations to determine energy requirements for weight maintenance for adults without obesity [11]. The calorie prescription for a 25% CR diet can be computed as TDEE × 0.75.

$$\mathit{\text{TDEE }}(\mathit{\text{kcal/day}})=1279+18.3(\mathit{\text{weight}},kg)+2.3(\mathit{\text{age}},y)-338(\mathit{\text{sex}}:1=\mathit{\text{female}},0=\mathit{\text{male}})$$ Equation 1.

$$\mathit{\text{TDEE }}(\mathit{\text{kcal}}/\mathit{\text{day}})=454+38.7(\mathit{\text{fat-free mass, kg}})-5.4(\mathit{\text{fat mass, kg}})+4.7(\mathit{\text{age}},y)+103(\mathit{\text{sex}}:1=\mathit{\text{female}},0=\mathit{\text{male}})$$ Equation 2.

The composition of the diet to support individuals undergoing CR can be diverse as no single diet or eating pattern is optimal for everyone. For example, upon initiation of the CR prescription in the CALERIE trials, study participants were provided with diets that were diverse in macronutrient composition, which consisted of a low-fat diet, Mediterranean diet, low-glycemic load diet, or vegetarian diet (Table 1). The goal was to prescribe a diet that not only provided the desired number of calories for the CR intervention, but also ensured satiety, adequate nutrition, and daily recommended intakes of vitamins and minerals.

Table 1.

Diet macronutrient composition from the CALERIE trials.

	Fat	Protein	Carbohydrate
Low-fat diet	20%	20%	60%
Mediterranean diet	35%	15%	50%
Low-glycemic	30%	30%	40%
Vegetarian diet	30%	20%	50%

Maintaining CR involves a thoughtful and intensive behavior change intervention. While CALERIE 1 provided evidence for the beneficial effects of a 25% CR, which resulted from both energy intake alone (diet) or in combination with aerobic exercise energy expenditure (EE), CALERIE 2 prescribed a 25% reduction in caloric intake without an exercise component. Ramping up to the desired calorie deficit is unnecessary, as the CALERIE trials demonstrated that an immediate 25% reduction was successful when incorporating a multifaceted behavior change and adherence program [12]. Strategies used in CALERIE to promote adherence included a short period of meal provision at the onset of the intervention, daily weighing, digital software to aid in diet tracking, and personalized counseling sessions to deliver a behavior change intervention [12]. Personalized counseling sessions occurred weekly for the initial four weeks, and tapered to biweekly for the first year and monthly for the second year, with additional sessions scheduled as needed [12]. However, even with these innovative and arguably extensive strategies to promote adherence to 25% CR, CR averaged 19.5 ± 0.8% over the first 6 months and declined further to 9.1 ± 0.7% for the remainder of the study [13].

1.3. Effects of CR on weight and body composition changes

Following the initial 6 months of CR in the CALERIE trials, body weight was reduced by 10% [14]. This weight loss included a 24% reduction in fat mass and 27% reduction in abdominal visceral fat [14]. Weight loss continued throughout the first year and resulted in a 5.4% reduction in percent body fat [15]. Thereafter, weight loss plateaued, and there were no further changes to body composition after year two [15]. At the end of the CALERIE trials, participants lost 10% of their baseline weight, which amounted to ~8 kg of body weight [15].

While CR greatly impacts human healthspan, a trial to investigate the effects of CR on human lifespan is not yet feasible. To fully elucidate the benefits and potential risks of CR for aging in humans, there is an important need to examine the extended effects of CR beyond weight loss. These may be best observed after the CR-induced weight loss reaches a plateau and is maintained with a new energy balance of energy intake and EE. The CALERIE trials included a period of weight loss (baseline to 12 months) followed by a period of weight loss maintenance (between months 12 and 24) with continued CR. The period of weight loss maintenance allowed for the long-term effects of CR to be isolated from short-term CR. This review describes the effects of CR on health outcomes and disease risk factors beyond weight loss (Figures 1 and 2) and offers insight for future directions in the field of CR. We refer to the 12 months from baseline as ‘in response to weight loss’ and 24 months from baseline as ‘in response to weight loss maintenance’. We also make comparisons to the ad libitum control group. Briefly, the ad libitum group was simply advised to continue their current dietary and lifestyle habits throughout study involvement ad libitum, meaning as they wished.

Figure 1.

CR-induced changes in physiological measures across a period of weight loss (0–12 months) and weight maintenance (0–24 months) in adults without obesity participating in CALERIE 2. Abbreviations: ↑ significant within-group increase, ↓ significant within-group decrease, ↔ no significant within-group change in markers from baseline to the time point of measurement within the CR group. Abbreviations: RMR (resting metabolic rate adjusted for body composition), TDEE (total daily energy expenditure adjusted for body composition), CVD (cardiovascular disease), LDL (low-density lipoprotein), HDL (high-density lipoprotein), AUC (area under the curve), T3 (triiodothyronine), TSH (thyroid-stimulating hormone), CRP (c-reactive protein), TNF-α (tumor necrosis factor alpha), WBC (white blood cell), ICAM-1 (intracellular adhesion molecule 1), LMC (lymphocyte and monocyte counts), CRF (cardiorespiratory fitness). *p < 0.05 between calorie restriction and ad libitum groups. ^ΨChanges in growth factors included reduced insulin-like growth factor (IGF) binding proteins (BP): IGFBP-1, IGFBP-3, IGF-1:IGFBP-1/3* ratios and transforming growth factor beta 1 (TGF-β1) at month 12, as well as reduced IGF-1, IGFBP-1*, IGFBP-3*, IGF-1:IGFBP-1*/3 ratios, TGF-β1, platelet-derived growth factor-AB, and cortisol* at month 24.

Figure 2.

CR-induced changes in behavioral and psychological, measures across a period of weight loss (0–12 months) and weight maintenance (0–24 months) in adults without obesity participating in CALERIE 2. Abbreviations: + significant within-group improved change, – significant within-group worsened change, ↔ no significant within-group change in markers from baseline to the timepoint of measurement within the CR group. *p < 0.05 between CR and ad libitum groups.

2. Effects of CR on energy metabolism

2.1. Introduction

Metabolism describes all life-sustaining processes involved in the production of adenosine triphosphate (ATP), the primary energy-generating molecule. TDEE encompasses the energy required to sustain all physiological and psychological functions during sleep and wake times, including at rest (resting metabolic rate; RMR), the thermic effect of food, and the energy costs of arousal and activity. The largest component of TDEE is RMR, accounting for 60% to 70% of TDEE [16]. Individual EE has been linked to lifespan, with the ‘the rate of living theory’ being among the most studied theories of aging. This theory suggests that the largest living species have shorter lifespans given that mass is the primary contributor to RMR and the largest component of the energy cost for sustaining life [17]. This theory also suggests there is a specific amount of energy available to expend throughout lifetime, and the rate at which this energy is expended determines lifespan [17,18]. As the mitochondria are the site of oxidative phosphorylation, the primary source of energy production, mitochondrial function is commonly implicated in the aging process. Aging is accompanied by a decrease in mitochondrial respiratory capacity, which reduces mitochondrial efficiency, yielding a smaller amount of ATP production for a given supply of oxygen [19]. Small percentages of oxygen consumption bypass oxidative phosphorylation and result in an accumulation of reactive oxygen species (ROS) [20]. Progressive mitochondrial inefficiencies, in turn, increase ROS and induce oxidative stress [21]. The ‘Oxidative Stress Theory of Aging’ proposes that excess production of ROS over time leads to oxidative damage to proteins, lipids, and deoxyribonucleic acids (DNA), resulting in abnormal cell, tissue, and organ function [22]. The basis of this theory is that an imbalance between ROS and antioxidants in the body results in a chronic state of oxidative stress at the cellular level that increases with age.

2.2. Effects of CR on RMR and TDEE

CR has been hypothesized to decrease the energy cost of metabolism. In the presence of an energy deficit, the body adapts by optimizing use of limited energy intake to support daily functions. As a result, metabolic adaptation is elicited, whereby the energy needed to sustain daily processes (TDEE) is below energy requirements. Studies have shown robust reductions in EE alongside CR [13,18,23]. After accounting for the reduction in energy requirements in response to weight loss, and a loss of fat and fat-free mass, the CALERIE trials found RMR to be reduced by 5.9% [13]. This metabolic adaptation to RMR was sustained in response to weight loss maintenance, but was not different from the ad libitum group [13]. The authors challenged that the lack of evidence for a prolonged metabolic adaptation to RMR following sustained CR was likely due to a lower level of adherence to the CR intervention as the trial progressed (year 1: ~15% to year 2: ~9%) [13]. Indeed, when examining a subset of highly adherent subjects, defined as >5% weight loss for the CR group and ≤5% weight loss for the ad libitum group), a metabolic adaptation during sleep (sleep EE) was observed in response to weight loss maintenance [18]. Metabolic adaptation was also observed for TDEE in the CR group, but not the ad libitum group, in response to weight loss and weight loss maintenance [18]. These findings indicate that declines in multiple components of TDEE contribute to the reduced EE and observed metabolic adaptation with CR.

2.3. Potential mechanisms of CR-induced metabolic adaptation

CR is hypothesized to induce metabolic adaptation in two ways. First, via central endocrine mechanisms that exist to conserve energy when available energy sources are scarce. Thyroid axis hormones, including thyroid stimulating hormone (TSH), triiodothyronine (T₃), and thyroxine (T₄), in conjunction with the sympathetic and parasympathetic nervous system, regulate metabolic rate and core body temperature [24]. Second, via alterations in energy usage at the cellular level that may lessen overall energy needs through increased mitochondrial uncoupling and an increase in mitochondrial biogenesis and subsequent remodeling [25,26].

2.3.1. Evidence to support a central mechanism of metabolic adaptation: effects of CR on circulating hormones and core body temperature

Previously, Plasma T₃ was shown to significantly reduce in response to weight loss (−18.4 ± 1.8 ng/dL) and weight loss maintenance (−25.0 ± 1.6 ng/dL) [9,13]. Unlike T₃, reductions in T₄ were only significant in response to weight loss maintenance (−0.73 ± 0.17 μg/dL) [13]. Reduced activities of the thyroid axis were not supported by changes to TSH concentrations, which were only different to the ad libitum group in response to weight loss (between-group difference: – 0.19 uIU/mL), but not weight loss maintenance [13].

The thyroid axis is also involved in the regulation of leptin, which is produced by adipose tissue and aids in hunger inhibition and energy balance regulation [27]. Concomitant with the loss of fat mass, significant reductions in circulating leptin were found in the CR group in response to weight loss (−11.0 ng/mL), which persisted in response to weight loss maintenance (−9.7 ng/mL) [28]. The observed decrease in leptin was significantly different between the CR and ad libitum groups, yet is not surprising given decreases in weight and fat mass achieved in the CR group [14,15,28]. Of note, the metabolic adaptation in sleep EE was associated with greater reductions in leptin, but not in thyroid axis hormones (T₃, T₄, TSH) in response to weight loss [18]. The relationship between leptin and sleep EE disappeared in response to weight loss maintenance, although a greater contribution from T₄ occurred [18]. While a previous study did not find an association between leptin and metabolic adaptation following three weeks of CR, the study restricted energy needs to 50% (29), a substantially larger degree of restriction than prescribed in CALERIE trials. Further, the CR period in this specific study was preceded by a 1-week overfeeding period (at +50% of energy needs), resulting in a 1.8 kg increase in body weight, which may impact the dynamic of leptin following CR induced weight loss [29]. Therefore, when adopting a more conservative CR approach, the mechanisms linking leptin to metabolic adaptation may be more apparent with short-term weight loss, compared to mediation by central mechanisms, notably thyroid hormones, after weight loss is maintained.

The reductions in EE have been supported by modest effects on core body temperature. Following 6 month of weight loss, 24-hour core body temperature significantly reduced (CR: −0.2 ± 0.05°C; CR + Ex: −0.3 ± 0.08°C) [9]. The CALERIE 2 trial similarly reported a reduction to core body temperature in the CR group in response to weight loss (−0.05 ± 0.02°C) and weight loss maintenance (CR: −0.05 ± 0.02°C), yet was not different from the ad libitum group [13,18]. The lack of observed effect on core body temperature may be attributed to a ceiling effect of reaching a lowered core body temperature after 6 months or due to the degree of CR achieved.

2.3.2. Evidence to support a cellular-level mechanism of metabolic adaptation: effects of CR on mitochondrial function and oxidative stress

Mitochondria are membrane-bound intracellular organelles that generate most of the chemical energy (i.e. ATP) needed to power biochemical reactions, primarily through the energy generating Krebs cycle and the electron transport chain. Mitochondrial biogenesis is the process by which cells increase mitochondrial mass, which is achieved, in part, from increased expression of genes responsible for encoding proteins that are related to mitochondrial function [26,30]. When mitochondrial biogenesis occurs, a more efficient coupling mechanism within the electron transport chain is produced. These efficiencies result in decreased whole-body oxygen consumption and a subsequent reduction in EE [21]. CR has been shown to stimulate mitochondrial biogenesis and enhance mitochondrial respiration [26]. These shifts toward greater efficiency are remarkable, since key mitochondrial enzymes of the Krebs cycle (citrate synthase and aconitase), β-oxidation (acyl-CoA dehydrogenase), and the electron transport chain (complex I–IV activity) were found to be unchanged following CR [25,26].

A reduction in whole-body EE results in a proportional reduction in ROS, deleterious by-products of oxidative phosphorylation. Declines in oxygen consumption result in lowered electron leakage, which are the foundation of oxygen-containing radicals [21]. ROS are maintained through scavenging enzymes and dietary antioxidants, but excessive ROS result in systemic oxidative stress and damage to protein, lipids, and DNA, to collectively accelerate the aging process [1,7]. Measurement of ROS is challenged by their short lifespan and rapid reactivity with proteins, lipids, and DNA [31]. Systemic or tissue-specific oxidative stress may be measured through stable biomarkers, such as isoprostanes, prostaglandin-like substances [32]. F₂-isoprostanes are readily considered the best available biomarkers of systemic oxidative stress, as they are clinically stable, specific products of peroxidation, and are present in detectable amounts in tissues and biological fluids [26]. Previously, reductions in oxidative stress assessed as F₂-isoprostane concentrations have been observed with CR. Concentrations of F₂-isoprostanes 2,3-dinor-iPF(2a)-III and iPF (2a)-III levels were reduced by 13% and 27%, respectively, in response to weight loss maintenance compared to the ad libitum group [33]. Together, these findings suggest that CR can significantly attenuate oxidative stress through a metabolic adaptation that results in whole-body reductions in oxygen consumption.

3. Effects of CR on cardiometabolic health

3.1. Cardiovascular health

Cardiovascular health is essential for healthy aging. In the modern environment, characterized by calorically-dense foods and physical inactivity, the prevalence of cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide [34]. The development of CVD is considered a multistage process involving atherosclerosis, hypertension, and vascular disease, and is indicative of an aging cardiovascular system via pathophysiological alterations to central and peripheral cardiac tissues [35]. Modifiable risk factors, such as increased adiposity and decreased muscle mass, increase risk for CVD through increased peripheral blood flow resistance, which leads to decreased left ventricular function [36,37]. However, more commonly, CVD develops peripherally through venous and arterial stiffening [38]. This phenomenon is classically characterized by accumulation of lipoprotein cholesterols, such as triglycerides and low-density lipoproteins (LDL) [39]. A high calorie and nutritionally poor diet exacerbates endothelial dysfunction, and, in turn, CVD risk through progressive insulin resistance [40], thereby connecting the cardiovascular system with the metabolic system.

CR, alongside improvements to diet quality, has been proposed as a mechanism for decreasing CVD risk to promote healthy aging [41]. Intensive and prolonged CR over 6 years was shown to provide a protective effect against structural and functional changes to peripheral atherosclerotic risk factors, including central left ventricular diastolic function and peripheral carotid artery intima-media thickness in adults without chronic disease [42]. The CALERIE trials suggest that CR reduces CVD risk in response to weight loss and weight loss maintenance compared to the ad libitum group [4]. CR decreased triglycerides, total cholesterol, and LDL cholesterol concentrations, while increasing high-density lipoprotein cholesterol concentrations [43]. Furthermore, significant improvements in blood pressure were observed in the CR group in response to weight loss and weight loss maintenance [13,28,44]. The estimated 10-year CVD risk was shown to significantly decline after 6 months by 30%, which persisted in response to weight loss maintenance [43,45]. These findings are striking considering participants were healthy adults without obesity.

3.2. Glycemic health

In the United States, 34.2 million Americans have diabetes, of whom 14.3 million are seniors aged 65 years or older [46]. The global prevalence of diabetes in adults is on the rise, doubling from 1980 to 2019 (4.7% to 9.3%), and is estimated to reach 10.2% by 2030 [47]. Diabetes commonly develops when there is a chronic imbalance between glucose availability and insulin production, which regulates glucose homeostasis. A type 2 diabetes diagnosis is often multifactorial, such as having a family history of disease, overweight or obesity, poor diet, and physical inactivity [48–51]. Aging itself is also a risk factor for the development of impaired glycemic health and increased risk of developing type 2 diabetes. Initial stages of the development of type 2 diabetes are characterized by resistance to insulin action on glucose uptake in peripheral tissues, which has been associated with changes to body composition, including increased central adiposity and decreased skeletal muscle mass [52]. As a result, hepatic glucose regulation is altered, followed by dysregulated insulin secretion from β-cells or β-cell death through age-related mitochondrial dysfunction, and reduced insulin sensitivity [53–55]. As diabetes leads to deleterious complications in cardiometabolic health, negative health effects may arise during the aging process if glycemic health is neglected [56]. Maintaining glycemic health and insulin sensitivity are therefore integral to healthy aging and overall healthspan as insulin regulates hepatic glucose production, glucose and fatty acid oxidation, energy storage, protein synthesis, and cell growth [57,58].

Several therapeutics are speculated to improve and combat the risk of diabetes development [59,60]. CR has been proposed as a noninvasive means of improving key regulators for maintenance of glycemic health, including the deregulated nutrient-sensing observed in aging through inhibition of insulin-like growth factor (IGF) signaling pathway and regulators of cellular metabolism [61–64]. Therefore, CR presents a unique opportunity to decrease the risk for development of type 2 diabetes. Following 6 months of CR, reductions in fasting insulin and the acute insulin response to an intravenous glucose load were found in young adults [65]. Further, significant improvements in the insulin sensitivity index (ISI; Δ = 2.0 ± 3.9), and significant decreases in fasting insulin concentration (Δ = −2.5 ± 3.9 μU/mL) and insulin area under the curve (AUC; Δ = −1.3 ± 2.1 × 10³ μU·min⁻¹·mL⁻¹) following an oral glucose tolerance test (OGTT) were observed in response to weight loss in older adults [66]. These findings were notably attributed to an increase in circulating concentrations of adiponectin, a regulatory protein of glucose concentration and insulin sensitivity [67]. Yet, improvements in the ISI were found to be more pronounced in response to weight loss maintenance compared to the ad libitum group (CR: Δ = 0.099 ± 0.015 and ad libitum: Δ = −0.013 ± 0.020), which highlights long-term implications of CR [44].

Although there exists some conjecture surrounding the long-term implications of CR on glycemic health, there has been speculation that a variation in the composition of the diet may be more beneficial for glucose control [68]. A 1-year randomized controlled trial of CR-induced weight loss examined diets with high glycemic load (HGL) or low glycemic load (LGL) at 30% CR [69,70]. Improvements to fasting glucose concentration (LGL: 6-month Δ = −1.8 ± 7.8% and 1-year Δ = 5.0 ± 9.9%; HGL: 6-month Δ = −2.5 ± 6.1% and 1-year Δ = −2.3 ± 6.2%), fasting insulin concentration (LGL: 6-month Δ = −25.4 ± 24.2% and 1-year Δ = −21.2 ± 16.7%; HGL: 6-month Δ = −14.9 ± 20.0% and 1-year Δ = −18.0 ± 15.0%), the homeostasis model assessment of insulin resistance, and OGTT insulin AUC were found within, but not between, LGL and HGL groups at 6 months and 1-year of CR [69]. Therefore, improvements to glucose and insulin or insulin sensitivity/resistance may not be due to superiority of dietary glycemic load. The degree of CR achieved was adequate enough to improve glycemic health as a result of weight loss in this population. Collectively, these findings are remarkable, as short-term CR (6 months to one year) was shown to have beneficial effects on glycemic health in healthy, younger adults without obesity.

4. Effects of CR on immune response, inflammation, and growth factors

4.1. Immune response and inflammation

Inflammation is a physiological response to molecular, cellular, or viral threats, and is characterized by immune responses designed to remove damaged tissue and foreign substances in the body [71,72]. Acute and chronic inflammatory states follow a harmonized process of increased blood flow to damaged tissue, allowing an influx of white blood cells and plasma proteins to initiate tissue repair in damaged areas [73]. Chronic inflammation represents sustained aggravation and a progressive alteration in the types of cells present at the localized site, which stresses both the localized and systemic environment [73]. These stressors may underpin the development of pathological states, including cardiometabolic diseases such as obesity, CVD, and type 2 diabetes [71]. Mechanistically, an inflammatory state is hypothesized to block metabolic signals that upregulate transcription of DNA, cytokine production, and cell survival, and leads to downregulation of mitochondrial proteins and the protein synthesis machinery [74,75]. Therefore, regulating and reducing inflammation may mitigate mitochondrial dysfunction that occurs in tandem with aging.

Inflammaging is a term to characterize low-grade systemic inflammation that progressively develops during biological aging [76]. Inflammaging is a by-product of degeneration of receptors that sense internal and external damage and activate immune responses [77]. Innate immune responses are the first line of defense against an antigen’s appearance in the body and occurs immediately or within hours. Adaptive immunity, however, involves acquired or specific immunity to the pathogen presented and is sustained long-term by memory T-cells [78]. Chronic stimulation of the innate immune system and decline in adaptive immunity create an inflammatory ‘storm’ that may accelerate biological aging [77]. The constant inflammatory state, coupled with a progressive inflammatory response, suppresses the ability to adapt to stressors and increases risk for age-related diseases [77].

Concerns about the potential harmful immunosuppressive effects of moderate-to-extreme CR have previously emerged from pre-clinical models [79,80]. Encouragingly, no effect on cell-mediated immunity assessed via antibody responses to three vaccines (Hepatitis A, tetanus/diphtheria, and pneumococcal) and delayed-type hypersensitivity skin response to three recall antigens (trichophyton, tetanus, and candida) was observed in response to weight loss maintenance [28]. In relation to innate immunity, CR significantly reduced circulating inflammatory markers, including total white blood cell lymphocyte and monocyte counts and monocyte chemoattractant protein-1 [28]. These observations showcase that the immediate and variable inflammatory response was unchanged with CR.

Leptin and fat mass have been previously hypothesized as the drivers of change in innate immunity, with improvements pointing to lower leptin concentration and decreased fat mass [28]. While there were observed concurrent declines in leptin and tumor necrosis factor-α (TNF-α), an inflammatory biomarker responsible for cellular signaling and subsequently necrosis or apoptosis of tissues/cells [73], in response to weight loss maintenance, peak reductions in circulating leptin in response to weight loss were not accompanied with declines in TNF-α [13,18]. It is possible that CR may alter neuroendocrine pathways by downregulating nutrient-sensing mechanisms that influence mitochondrial function, redox status, and inflammatory gene expression, thereby attenuating inflammation [28].

4.2. Growth factors

Growth factors are naturally occurring proteins that can stimulate/inhibit cell proliferation and occasionally impact cellular differentiation [81]. The temporal expression of growth factors is involved in inflammation development seen in several diseases and has been implicated in aging [82]. Decelerated aging is thought to occur through downregulation of growth factor pathways (IGF-1), upregulation of autophagic and apoptotic pathways, increased resistance to toxic agents, and increased genome stability [63,83].

CR resulted in significantly reduced IGF binding proteins (BP), IGFBP-1, IGFBP-3, IGF-1:IGFBP-1/3 ratios, and transforming growth factor beta 1 in response to weight loss and weight loss maintenance, as well as IGF-1 and platelet-derived growth factor-AB in response to weight loss maintenance only [84]. Despite CR-induced reductions, differences between the CR group and ad libitum group were only observed for IGFBP-3 in response to weight loss and IGFBP-1, IGF-1/IGFBP-1 ratio, and cortisol (which regulates IGFBP and IGF pathways) in response to weight loss maintenance [84,85]. If sustained over the long-term, CR may be an appropriate mechanism to reduce IGFBP-1, through which IGF-1 activity is inhibited, to improve inflammation and inflammation-associated diseases.

5. Effects of CR on physical fitness

Maintaining and preserving physical fitness and function with age is recommended and vital for health. Aging coincides with unavoidable losses to physical fitness and function, which are essential for activities of daily living [86]. Maximal strength and power have been observed to decrease with age [87]. Although regular physical activity and maintenance of physical fitness are important predictors of healthy aging, older adults exhibit the lowest adherence to the physical activity guidelines in comparison to other age groups [88,89]. Low levels of physical activity and physical fitness lead to an increased risk for sarcopenia, low bone mineral density, and falls [90,91]. Furthermore, older adults are the most vulnerable to fall risk, accounting for the second leading cause of unintentional fatal and nonfatal injuries among older adults worldwide [92]. As long-term health complications arise with aging due to inability to perform activities of daily living, the maintenance of physical fitness, strength, and function are vital for prolonged and healthful aging [93].

Exercise programs are often viewed as primary means for improving and preserving physical fitness and function throughout the aging continuum [94]. CR-induced weight loss has also emerged as an effective strategy. However, considering the changes to body composition that occur with CR (e.g. loss of muscle mass and bone mineral density), it is important to understand the implications of CR on physical fitness and strength [95]. In the CALERIE trials, cardiorespiratory fitness as measured by VO_2max (L·min⁻¹) decreased in response to weight loss and weight loss maintenance, with a significant difference from the ad libitum group only in response to weight loss [96]. However, when VO_2max was expressed relative to body weight (mL·kg⁻¹·min⁻¹), it was found to be increased in response to both weight loss and weight loss maintenance by 2.2 mL·kg⁻¹·min⁻¹ and 1.9 mL·kg⁻¹·min⁻¹, which was significantly different compared to the ad libitum group [96]. Similarly, CR was found to decrease absolute strength of knee flexion and extension in response to weight loss and weight loss maintenance, but it was increased from baseline when expressed relative to body weight [96]. These findings suggest that physical fitness and strength are potentially preserved with CR even in the presence of reductions in lean body mass. CR-induced reductions in body weight may enable greater economy of movement that effectively offsets lowering of absolute VO_2max when accounting for decreased body weight (relative VO_2max).

Exercise was not a structured component of the 2-year CALERIE trial but it might be an important consideration for elderly individuals as it may aid in preserving or increasing lean body mass during CR [14]. CR in conjunction with aerobic exercise was piloted in the phase 1 trials of CALERIE. While CR +EX produced comparable changes to body weight, body composition, and physical strength, greater improvements in absolute VO_2peak (10.4%) and relative VO_2peak (22.5%) were noted when exercise was added to CR [97]. Therefore, implementing exercise alongside CR may provide additive benefits beyond weight loss to improve physical fitness and function. This may be especially important in groups most vulnerable to muscle mass and bone mineral density loss, such as aging adults, where preservation and maintenance of physical fitness and strength are primary contributors to sustaining physical ability.

6. Effects of CR on mental health and health behaviors

6.1. Mental health

Deterioration of mental health and increased prevalence of mental illnesses are among the most common causes of disability. Nearly 15% of adults aged 50 years and older experience a mental health complications, most commonly anxiety, severe cognitive impairment, and mood disorders, such as depression or bipolar disorder [98]. Aging is often associated with deterioration of mental health, in part due to declines in cognitive function and physical health that accompany aging-related physiological and social changes [99]. In turn, worsened mental health and mental illness can limit adherence to health-promoting activities and further impact physical health. This vicious cycle of mental and physical deterioration exacerbates the progression of chronic diseases and may challenge treatment [100]. Given the importance of psychosocial and physical functioning, multiple national recognized agencies, such as Healthy People 2020, White House Conference on Aging, and the United States Surgeon General, have identified the mental health of aging adults in the United States as a priority.

CR has been hypothesized to have beneficial effects on the brain through neural signaling and molecular pathways that may enhance cerebral blood flow, blood-brain barrier function, and changes in neuro-inflammation [101,102]. One of the leading theories suggests that CR increases neurogenesis (the growth and development of nervous tissue) in the hippocampus, which is correlated with depression and critical for mood [101,102]. CR originally posed concerns in relation to mental wellness as worsened depression, anxiety, and mood were observed in a study of severe CR [103]. The CALERIE trials, which employed more conservative CR in a relatively young population free from age-related cognitive impairment/decline, revealed no adverse changes to cognitive performance. Spatial working memory, as well as attentional, selective interpretation, and memory bias on a series of tests assessing items or words related to depression, body size or shape, and food were not affected [104]. This is encouraging since obsessive preoccupations with food and body weight may cause cognitive impairments as a result of dietary restriction [105]. Further, superior improvements to self-reported general health, overall mood, and tension were observed in response to weight loss maintenance between CR and ad libitum groups [106]. It remains plausible that other behavioral and physiological factors may be at play in managing mental health, especially during CR-induced weight loss. However, a ceiling effect for quality of life may have been observed during the trials due to measurement limitations of assessment instruments and/or higher ratings on quality-of-life measures upon CR initiation.

6.2. Health behaviors

Growing evidence supports the role of health behaviors, including nutrition, physical activity, and sleep, in healthy aging and as preventive measures against several non-communicable diseases and disabilities. Health behaviors are often intertwined, and deteriorations in one domain are likely to have widespread implications on others. Therefore, maintaining or improving health behaviors as aging progresses is important for the conservation of an overall healthy lifestyle and healthspan.

Health behaviors are often altered with age due to progressive physiological changes. Aging has been associated with changes in perception of flavor and aroma that challenge existing feeding systems, including alterations in taste receptors, nutrition behaviors, and food preferences [107]. With advancing age, perceived and actual barriers to sitting and non-sitting activities may also widen the divergence between physical activity levels and sedentary behavior, including increased sitting to manage conditions such as aches and pains, poor health, and a lack of energy [108]. These physical health conditions, in addition to a deteriorating mental health, disrupted circadian rhythms, and altered hormonal production, may explain why elderly individuals report some form of sleep difficulty [109]. Examples include longer sleep onset times, longer duration in bed, more interruptions throughout the night, earlier wake up times, and more daytime naps [109]. Lastly, the natural physical and physiological declines, as well as illnesses, disabilities, medications, and surgeries that may occur with age, affect sexual health and function [110,111].

CR has been shown to exert beneficial effects on several health behaviors, with minimal adverse effects on others. From a dietary and nutrition perspective, an important focus when restricting food intake is eliminating negative effects on obsessions with food and disordered eating behaviors. In both the pilot and multi-site trials, CALERIE participants did not exhibit any signs of eating disorder pathology prior to participation in the CR intervention, and no eating disorder symptomatology developed in response to CR [4,112]. Contrarily, improvements to self-efficacy for regulating food intake and dietary restraint (conscientiously restrict or control food intake) were observed in response to weight loss and weight loss maintenance [113]. Interestingly and important, perceived hunger was unchanged between groups, however, small increases in dietary disinhibition (the tendency to overeat) were observed, although these remained within normal limits at the end of the trial [4]. Of reassurance, despite no prescriptive exercise interventionsand self-reported decreases in physical activity, objective physical activity levels in response to weight loss and weight loss maintenance remained unchanged [95]. However, there was an observed reduction in activity EE, which may be attributed to reductions in spontaneous physical activity (unconscious drive for movement such as fidgeting) or increased muscle efficiency [96]. In relation to sleep, prolonged CR did not adversely influence sleep quality or duration [106]. In fact, sleep may have contributed to the observed improvements in mental health or, at least, lessened negative mental health outcomes that often present with sleep disruption [114]. Finally, CR did not induce negative changes to sexual function, yet resulted in small improvements to sexual drive and sexual relationship in response to weight loss maintenance [106]. These findings support favorable changes to all health behaviors with CR, and no stimulation of assessed patterns of eating disorder behaviors or deleterious body image perceptions.

7. Sustained effects of CR

As an ancillary study to CALERIE 2, the lasting effects of CR were measured for two years after formal engagement in the CR intervention ended [115]. Body weight, body composition, EE, health behaviors, and psychological function were examined in twenty-nine adult men and women, both one and two years after completion of the initial two-year intervention [115].

Findings from the follow-up period elucidated that the prolonged effects of CR may be partially mitigated once a formal CR intervention is discontinued. While energy intake was not formally measured in the follow up study, assumptions were made that the degree of CR was substantially less, or discontinued, given the regain in body weight. Participants in the CR group regained 54% of their initial weight two years after completing the formal intervention (hereby referred to as follow-up) [115]. Despite gaining approximately half of the weight lost, weight remained significantly lower than the ad libitum group. Notably, percent body fat also remained significantly lower at follow-up compared to baseline and to the ad libitum group, and 27% of fat-free mass was regained at follow-up [115].

The robust energy reductions in response to CR were partially maintained at two years follow-up. While no significant absolute changes in 24-hour EE were observed from baseline to the 1- and 2-year follow-up, EE during sleep remained significantly reduced from baseline in the CR group at both time points [115]. Changes to sleep EE were not different compared to the ad libitum group, however there was a between-group difference in the overall mean metabolic adaptation for sleep EE (CR group: −91 ± 18 kcal/d; ad libitum group: −23 ± 23 kcal/d; P= 0.03) across the 2-year intervention and 2-year and follow-up [115]. Thus, providing the first objective evidence of a persistent metabolic adaptation two years following a 2-year prescribed CR intervention.

In relation to eating behaviors, higher cognitive restraint (stable disposition to limit food intake) persisted after two years follow-up in the CR group, and was differential to the ad libitum group [115]. Notably, the mean change for ‘avoidance of forbidden foods’ (internal dietary rules regarding unpermitted foods) in the CR group was higher at follow-up periods compared to baseline, and may have driven, in part, the observed persistent changes in eating behaviors [115]. In relation to physical activity, activity EE was significantly greater compared to baseline in the CR group after two years of follow-up [115]. While this was not differential to the ad libitum group, it indicates that those in the CR group returned to their habitual physically activity levels, which may have assisted in the partial regain of fat-free mass.

Collectively, these data support beneficial weight, metabolic, and behavioral changes when participants remain in energy balance and in the presence of metabolic adaptation two years after cessation of a two-year moderate CR intervention.

8. Conclusion

The health effects and safety of CR have been elegantly described throughout the rigorous trials of the CALERIE consortium. Sustained CR over two years has proven beneficial in preventing the development of age-related diseases and biomarkers of disease risk, even in healthy individuals free from chronic disease. The benefits include reductions to adiposity, EE, oxidative stress, blood pressure, lipid markers, regulators of glycemic health, inflammatory markers, and growth factors. These findings were coupled with improvements to relative cardiorespiratory fitness, physical strength, and psychological markers of general health, as well as dietary restraint, food regulation self-efficacy, and sexual drive and relationship.

9. Expert opinion

CR presents a novel and effective therapeutic approach for promoting healthspan and biomarkers of lifespan. Given the benefits observed in the CALERIE trials, individuals may eagerly wish to self-administer CR. These desires may be driven, in part, by news outlets and social media that have frequently misinterpreted or extrapolated findings of CR studies to indicate extended lifespan [116]. However, randomized controlled trials monitoring individuals undergoing CR until death are unlikely, and long-term health effects of prolonged CR remain unknown. Self-prescription of CR is not advised for healthy persons without medical oversight [116]. Monthly follow-up and routine medical examinations are advisable to monitor body composition, cardiometabolic and inflammatory profiles, physical fitness, lifestyle behaviors, and mental health.

Innovative features of the CALERIE study may be transferable to real-life practice when prescribing CR [12]. For example, providers can offer intensive mixed format programs, such as individual or group counseling sessions. Individual sessions may be used to monitor and tailor the CR prescription, and group counseling sessions may be used to deliver educational materials, learn problem-solving skills, and foster social support for maintaining CR. While these formats were found to be effective in CALERIE and other clinical trials, such as the Diabetes Prevention Program (DPP) and Action for Health in Diabetes (Look AHEAD) [117,118], frequent follow-up visits are not always practical in a busy clinical practice. Often, providers have short consultation times and extended durations between follow-up visits. More modern approaches, such as telemedicine, can fulfil this gap and may be beneficial for implementing CR programs in a practical real-world setting.

Telemedicine is an invaluable tool not only allowing for remotely maintaining care of patients, but also for the transmission of health information from patient to provider when the provider and/or patient are not physically present. Cellular enabled technology, such as an electronic scale, can link with telemedicine applications allowing a provider to remotely track a patients’ body weight. The ability to remotely monitor weight can also allow for interpretation of body weight in relation to anticipated weight changes with a CR prescription. Since body weight change was used as a measure of adherence in the CALERIE studies [12], this monitoring may allow for a provider to assess whether an individual is, or is not, adherent to the prescribed CR goal. Ecological momentary assessment applications integrated into a smart/mobile device allow for assessment of behavioral and cognitive processes in their natural setting [119]. This assessment can be particularly beneficial as it provides an opportunity for individuals to record food intake, rate hunger and satiety, and graphically view these outcomes over time. As such, providers with access to a bevy of real-time information allows for efficient and continual monitoring and evaluation of a prescribed CR program.

In response to a case of sub-optimal adherence to a prescribed CR program, the provider and patient would look to a pre-established list of options within a ‘toolbox’. These are pre-determined options that are used to increase the intensity of the intervention and to achieve the expected weight gain. The available toolbox options are typically jointly agreed upon by the provider and patient. A variety of ‘open’ and ‘closed’ strategies (Figure 3), can be immediately and effectively deployed in real-time to overcome obstacles. When low-to-moderate (i.e. open) toolbox strategies falter in reaching a desired weight, more intensive approaches (i.e. closed), such as partial meal replacements or full food provision, are recommended. These can be facilitated by additional provider support such as from a registered dietitian or nutritionist. Given the widespread implications of CR, referral to other specialists, such as exercise specialists and psychologists, may also be appropriate and in support of a multifaceted healthcare approach. In CALERIE, toolbox strategies were trialed for one to two weeks. This allows time to implement and evaluate the effectiveness of the strategy, and to reevaluate the need for additional toolbox options if evidence of weight change becomes present.

Figure 3. Troubleshooting problems of sub-optimal adherence to 25% calorie restriction.

(Adapted from Rickman AD, Williamson DA, Martin CK, Gilhooly CH et al. The CALERIE study: design and methods of an innovative 25% caloric restriction intervention. Contemp clin trials. 2011 Nov; 32(6): 874–881 [14].). ‘Open Toolbox’ strategies (less intensive) are applied immediately in the case of suboptimal adherence; that is, weight outside a pre-determined range or unmet dietary changes. ‘Closed Toolbox’ strategies (more intensive) should be considered approximately five weeks into CR, and discontinued when the patient no longer meets criteria necessary to utilize the indicated options in the toolbox.Reprinted from Contemp Clinical Trials, 32/6, Author(s), The CALERIE Study: design and methods of an innovative 25%caloric restriction intervention, 874–81, Copyright (2011), with permission from Elsevier.

When prescribing CR, there should be a focused emphasis that weight loss will eventually plateau, after which weight loss maintenance may be used as a marker to indicate that CR is being sustained. Given the potential challenges in sustaining CR, alternative strategies that similarly promote beneficial health effects on aging should be explored. Recently, intermittent fasting and time-restricted eating, where food consumption is limited to a fixed eating window, has emerged as a popular strategy to reduce weight and improve age-related cardiometabolic health outcomes [120]. To date, the most rigorous randomized controlled trial that examined the effects of alternate day fasting found that weight loss, markers of cardiovascular health, regulators of glucose control, and inflammation were similar for participants in an alternate day fasting group compared to a traditional CR group at 6 and 12 months [121,122]. While novel approaches may prove promising on their own, the ability to compare alternative dietary approaches to traditional CR, as performed in CALERIE, would be impactful to identify the attenuation or amplification of their benefits on healthspan and biomarkers of lifespan.

The National Institutes of Health recently announced an exciting call for proposals to support planning grants to discover novel dietary practices (i.e. dietary practices that modify the amount, timing, or composition of nutrient intake such as intermittent fasting). The design of these approaches is to be compared to traditional CR and examined over longer periods (5 years). In addition, these new clinical trials are set to commence in July 2021 and will be conducted in independent groups of younger and older adults, which will seek to examine mechanisms that influence human healthspan and biomarkers of lifespan. The future of nutritional interventions that support healthy aging in humans is exciting. Seeking a personalized, sustainable diet with optimum health benefits for individuals across the lifespan remains a priority for science and medicine over the long-term.

Article highlights.

• Calorie restriction (CR) is an effective dietary intervention to promote healthspan and biomarkers of lifespan.

• Moderate CR results in beneficial changes to adiposity, energy metabolism, oxidative stress, blood pressure and lipid profile, glycemic markers, the inflammatory milieu, growth factors, physical fitness, eating behaviors, psychological measures of general health, sexual drive, and sexual relationship.

• CR is not approved as a self-administered therapeutic and should be implemented under direct medical supervision and as part of a multidisciplinary healthcare approach.

• Sustaining moderate CR can be difficult. Novel dietary approaches that may equally or more practically mimic the health benefits of CR are needed and imminent.