Al's CR updates

[AlPater]

Associations between fruit intake and risk of diabetes in the AusDiab cohort.
Bondonno NP, Davey RJ, Murray K, Radavelli-Bagatini S, Bondonno CP, Blekkenhorst LC, Sim M, Magliano DJ, Daly RM, Shaw JE, Lewis JR, Hodgson JM.
J Clin Endocrinol Metab. 2021 Jun 2:dgab335. doi: 10.1210/clinem/dgab335. Online ahead of print.
PMID: 34076673
Abstract
Background: Fruit, but not fruit juice, intake is inversely associated with type 2 diabetes mellitus (T2DM). However, questions remain about the mechanisms by which fruits may confer protection. Aims were to examine associations between intake of fruit types and 1) measures of glucose tolerance and insulin sensitivity and 2) diabetes at follow-up.
Methods: Among participants of the Australian Diabetes, Obesity and Lifestyle Study, fruit and fruit juice intake was assessed by food frequency questionnaire at baseline. Associations between fruit and fruit juice intake and 1) fasting plasma glucose, 2-h post-load plasma glucose, HOMA2 of β-cell function (HOMA2-%β), HOMA2 of insulin sensitivity (HOMA2-%S), and fasting insulin levels at baseline and 2) the presence of diabetes at follow-up (5 and 12 years) were assessed using restricted cubic splines in logistic and linear regression models.
Results: This population of 7,675 Australians (45% males) had a mean±SD age of 54±12 years at baseline. Total fruit intakes were inversely associated with serum insulin and HOMA2-%β, and positively associated with HOMA2-%S at baseline. Compared to participants with the lowest intakes (quartile 1), participants with moderate total fruit intakes (quartile 3) had a 36% lower odds of having diabetes at 5 years [OR (95% CI): 0.64 (0.44, 0.92)], after adjusting for dietary and lifestyle confounders. Associations with 12-year outcomes were not statistically significant.
Conclusion: A healthy diet including whole fruits, but not fruit juice, may play a role in mitigating T2DM risk.
Keywords: 2-h post-load plasma glucose; Fasting plasma glucose; HOMA2 of insulin sensitivity (HOMA2-%S); HOMA2 of β-cell function (HOMA2-%β); fasting insulin levels.

Changes in serum thyroid function predict cognitive decline in the very old: longitudinal findings from the Newcastle 85+ study.
Gan EH, Jagger C, Yadegarfar ME, Duncan R, Pearce S.
Thyroid. 2021 Jun 2. doi: 10.1089/thy.2020.0596. Online ahead of print.
PMID: 34074153
Abstract
Background: Low serum TSH has been associated with an increased risk of cognitive impairment in observational studies of older individuals but the mechanism underlying this is unclear. We investigated the association between changes in thyroid status and cognitive impairment in very old adults, using prospective data from the Newcastle 85+ study.
Method: A cohort of 85-year-old individuals was assessed for health status and thyroid function. Complete data from a comprehensive multi-dimensional measure of health and repeat thyroid function were available for 642 participants with normal free thyroid hormones and TSH levels ranging between 0.1-10mU/L. Cognitive performance, assessed using Mini-Mental State Examination (MMSE) and Cognitive Drug Research battery was examined using linear mixed, logistic regression and Cox proportional hazard models in relation to baseline and 3-year changes in serum TSH, free T4 and free T3.
Results: Over 3 years, declining serum TSH was associated with reductions in free T4 and free T3, and an increased risk of incident cognitive impairment by 5 years [OR1.77 (95% CI: 1.19-2.61); p=0.004]. Greater reduction in MMSE score was associated with larger TSH decline, at 3 (p= 0.001) and 5 years (p<0.001), respectively. Steady free T4 concentrations were found in participants with rising TSH.
Conclusions: In contrast to physiological expectation, in this group of 85-year olds, a declining serum TSH was associated with reductions in free thyroid hormones over time. A decreasing serum TSH trajectory over time anticipated cognitive decline in later life. Declining TSH concentrations are a biomarker for cognitive impairment in later life.

Depression and Vegetarians: Association between Dietary Vitamin B6, B12 and Folate Intake and Global and Subcortical Brain Volumes.
Berkins S, Schiöth HB, Rukh G.
Nutrients. 2021 May 24;13(6):1790. doi: 10.3390/nu13061790.
PMID: 34073949
Abstract
Deficiency of vitamin B6 and vitamin B12, mostly in vegetarians, is found to be associated with depression and adverse neurological function. We investigated whether vitamin B6, B12, and folate have an effect on brain structure, especially among depressed people who follow a specific diet. The study sample comprised 9426 participants from the UK Biobank cohort with a mean age of 62.4 years. A generalized linear model controlling for age, sex, body mass index, ethnicity, town send deprivation index, educational qualification, smoking, and alcohol intake was used to test the association between study groups and structural brain volumes. Depression was more prevalent, and intake of vitamin B6 and B12 was lower among vegetarians, while non-vegetarians had a lower intake of folate. Overall, no significant association was observed between vitamin B6, B12, and folate intakes and both global and subcortical brain volumes among participants with depression. However, vitamin B12 intake was positively associated with right pallidum among non-depressed participants, and a significant interaction between vitamin B12 intake and depression status on the right pallidum was observed. Also, a significant interaction between folate intake and depression status on grey matter (GM) volume and left thalamus was observed. Upon diet stratification, folate intake is associated with total brain volume and GM volume among vegetarians with depression. Furthermore, no significant associations were observed for subcortical regions. Our findings suggest that dietary intake of vitamin B6 and B12 might have an effect on brain structure. Vegetarians, particularly those who suffer from depression may benefit from supplementing their diets with vitamins B6, B12, and folate to ensure brain health. Further studies, especially with a larger sample size and longitudinal design, are needed to confirm these findings.
Keywords: brain structure; depression; vegetarians; vitamin B12; vitamin B6.

Tropical Oil Consumption and Cardiovascular Disease: An Umbrella Review of Systematic Reviews and Meta Analyses.
Unhapipatpong C, Shantavasinkul PC, Kasemsup V, Siriyotha S, Warodomwichit D, Maneesuwannarat S, Vathesatogkit P, Sritara P, Thakkinstian A.
Nutrients. 2021 May 4;13(5):1549. doi: 10.3390/nu13051549.
PMID: 34064496 Review.
Abstract
The health effects of saturated fat, particularly tropical oil, on cardiovascular disease are unclear. We investigated the effect of tropical oil (palm and coconut oils), lard, and other common vegetable oils (soybean and rice bran oils) that are widely used in tropical and Asian countries on lipid profiles. We performed an umbrella review of meta-analyses and systematic reviews. Electronic databases (Medline, Scopus, Embase, and Cochrane) were searched up to December 2018 without language restriction. We identified nine meta-analyses that investigated the effect of dietary oils on lipid levels. Replacement of polyunsaturated fatty-acid-rich oils (PUFAs) and monounsaturated FA-rich oils (MUFAs) with palm oil significantly increased low-density lipoprotein cholesterol (LDL-c), by 3.43 (0.44-6.41) mg/dL and 9.18 (6.90-11.45) mg/dL, respectively, and high-density lipoprotein cholesterol (HDL-c), by 1.89 (1.23-2.55) mg/dL and 0.94 (-0.07-1.97) mg/dL, respectively. Replacement of PUFAs with coconut oil significantly increased HDL-c and total cholesterol -by 2.27 (0.93-3.6) mg/dL and 5.88 (0.21-11.55) mg/dL, respectively-but not LDL-c. Substituting lard for MUFAs and PUFAs increased LDL-c-by 8.39 (2.83-13.95) mg/dL and 9.85 (6.06-13.65) mg/dL, respectively-but not HDL-c. Soybean oil substituted for other PUFAs had no effect on lipid levels, while rice bran oil substitution decreased LDL-c. Our findings show the deleterious effect of saturated fats from animal sources on lipid profiles. Replacement of unsaturated plant-derived fats with plant-derived saturated fats slightly increases LDL-c but also increases HDL-c, which in turn may exert a neutral effect on cardiovascular health.
Keywords: cardiovascular disease; coconut oil; lard; lipid; palm oil; rice bran oil; soybean oil; tropical oil; vegetable oil.

The Leading Causes of Death in the US for 2020.
Ahmad FB, Anderson RN.
JAMA. 2021 May 11;325(18):1829-1830. doi: 10.1001/jama.2021.5469.
PMID: 33787821 No abstract available.
https://jamanetwork.com/journals/jama/fullarticle/2778234
"Provisional estimates indicate a 17.7% increase in the number of deaths in 2020 (the increase in the age-adjusted rate was 15.9%) compared with 2019, with increases in many leading causes of death.1 The provisional leading cause-of-death rankings for 2020 indicate that COVID-19 was the third leading cause of death in the US behind heart disease and cancer.1"

Goji berry (Lycium barbarum L.) juice reduces lifespan and premature aging of Caenorhabditis elegans: Is it safe to consume it?
de Freitas Rodrigues C, Ramos Boldori J, Valandro Soares M, Somacal S, Emanuelli T, Izaguirry A, Weber Santos Cibin F, Rossini Augusti P, Casagrande Denardin C.
Food Res Int. 2021 Jun;144:110297. doi: 10.1016/j.foodres.2021.110297. Epub 2021 Mar 9.
PMID: 34053563
Abstract
Goji berry fruit is considered a healthy food. However, studies on its effects on aging and safety are rare. This study is the first to evaluate the effects of goji berry juice (GBJ) on oxidative stress, metabolic markers, and lifespan of Caenorhabditis elegans. GBJ caused toxicity, reduced the lifespan of C. elegans by 50%, and increased the reactive oxygen species (ROS) production by 45-50% at all tested concentrations (1-20 mg/µL) of GBJ. Moreover, the highest concentration of GBJ increased lipid peroxidation by 80% and altered the antioxidant enzymes. These effects could be attributed to a pro-oxidant effect induced by GBJ polyphenols and carotenoids. Moreover, GBJ increased lipofuscin, glucose levels, number of apoptotic bodies, and lipase activity. The use of mutant strains demonstrated that these effects observed in the worms treated with GBJ were not associated with the Daf-16/FOXO or SKN-1 pathways. Our findings revealed that GBJ (mainly the highest concentration) exerted toxic effects and promoted premature aging in C. elegans. Therefore, its consumption should be carefully considered until further studies in mammals are conducted.
Keywords: Antioxidant enzymes; Apoptosis; Lipofuscin; Oxidative stress; Polyphenols.

https://www.huffpost.com/entry/products-tips-for-back-pain_l_609aaf7fe4b099ba752f2f40

Want To Know If You Have Good Gut Health? Try Turning Your Poop Blue.
This experiment tests your gut microbiome, which plays a role in your digestion, mood and more. Here's why and how to do it.
By 
Natasha Hinde
05/19/2021 
https://www.huffpost.com/entry/gut-health-poop-blue_l_60a40353e4b0daf2b5a73d35

Restoration of energy homeostasis by SIRT6 extends healthy lifespan.
Roichman A, Elhanati S, Aon MA, Abramovich I, Di Francesco A, Shahar Y, Avivi MY, Shurgi M, Rubinstein A, Wiesner Y, Shuchami A, Petrover Z, Lebenthal-Loinger I, Yaron O, Lyashkov A, Ubaida-Mohien C, Kanfi Y, Lerrer B, Fernández-Marcos PJ, Serrano M, Gottlieb E, de Cabo R, Cohen HY.
Nat Commun. 2021 May 28;12(1):3208. doi: 10.1038/s41467-021-23545-7.
PMID: 34050173
https://www.nature.com/articles/s41467-021-23545-7.pdf
Abstract
Aging leads to a gradual decline in physical activity and disrupted energy homeostasis. The NAD+-dependent SIRT6 deacylase regulates aging and metabolism through mechanisms that largely remain unknown. Here, we show that SIRT6 overexpression leads to a reduction in frailty and lifespan extension in both male and female B6 mice. A combination of physiological assays, in vivo multi-omics analyses and 13C lactate tracing identified an age-dependent decline in glucose homeostasis and hepatic glucose output in wild type mice. In contrast, aged SIRT6-transgenic mice preserve hepatic glucose output and glucose homeostasis through an improvement in the utilization of two major gluconeogenic precursors, lactate and glycerol. To mediate these changes, mechanistically, SIRT6 increases hepatic gluconeogenic gene expression, de novo NAD+ synthesis, and systemically enhances glycerol release from adipose tissue. These findings show that SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging.

Modifications to residential neighbourhood characteristics and risk of 79 common health conditions: a prospective cohort study.
Kivimäki M, Batty GD, Pentti J, Nyberg ST, Lindbohm JV, Ervasti J, Gonzales-Inca C, Suominen SB, Stenholm S, Sipilä PN, Dadvand P, Vahtera J.
Lancet Public Health. 2021 Jun;6(6):e396-e407. doi: 10.1016/S2468-2667(21)00066-9.
PMID: 34051163
Abstract
Background: Observational studies have identified a link between unfavourable neighbourhood characteristics and increased risk of morbidity, but it is unclear whether changes in neighbourhoods affect future disease risk. We used a data-driven approach to assess the impact of neighbourhood modification on 79 health outcomes.
Methods: In this prospective cohort study, we used pooled, individual-level data from two Finnish cohort studies: the Health and Social Support study and the Finnish Public Sector study. Neighbourhood characteristics (mean educational level, median income, and employment rate of residents, and neighbourhood green space) and individual lifestyle factors of community-dwelling individuals were assessed at baseline (at different waves starting between 1998 and 2013). We repeated assessment of neighbourhood characteristics and lifestyle factors approximately 5 years from each baseline assessment, after which follow-up began for health conditions diagnosed according to the WHO International Classification of Diseases for 79 common health conditions using linkage to electronic health records. We used Cox proportional hazard regression models to compute adjusted hazard ratios (HRs) of incident disease associated with neighbourhood characteristics and changes in neighbourhood characteristics over time and logistic regression analysis to compute adjusted odds of association between changes in neighbourhood characteristics and individual lifestyle factors.
Findings: 114 786 individuals (87 012 [75·8%] women; mean age 44·4 years [SD 11·1]) had complete data and were included in this cohort study. During 1·17 million person-years at risk, we recorded 164 368 new-onset health conditions and 3438 deaths. Favourable changes in neighbourhood characteristics were associated with reduced risk of all-cause mortality and incidence of 19 specific health conditions. Unfavourable changes were correspondingly associated with increased risk of mortality and 27 specific health conditions. Among participants who did not move residence during the observation period, relative to individuals who continually lived in disadvantaged neighbourhoods, those who experienced favourable modifications in neighbourhood characteristics had a lower risk of future diabetes (HR 0·84, 95% CI 0·75-0·93), stroke (0·49, 0·29-0·83), skin disease (0·72, 0·53-0·97), and osteoarthritis (0·87, 0·77-0·99). Living in a neighbourhood with improving characteristics was also associated with improvements in individual-level health-related lifestyle factors. Among participants who lived in advantaged residential environments at baseline, unfavourable changes in neighbourhood characteristics were associated with an increased risk of diabetes, stroke, skin disease, and osteoarthritis compared with individuals who lived in advantaged neighbourhoods throughout the study period.
Interpretation: Favourable modifications to residential neighbourhoods showed robust, longitudinal associations with a range of improvements in health outcomes, including improved health behaviours and reduced risk of cardiometabolic, infectious, and orthopaedic conditions.

Long-Term Effect of Salt Substitute on All-Cause and Cardiovascular Disease Mortality: An Exploratory Follow-Up of a Randomized Controlled Trial.
Sun H, Ma B, Wu X, Wang H, Zhou B.
Front Cardiovasc Med. 2021 May 17;8:645902. doi: 10.3389/fcvm.2021.645902. eCollection 2021.
PMID: 34079827 Free PMC article.
Abstract
Background: Salt substitute, a strategy for salt reduction, has been shown to decrease blood pressure and the incidence of hypertension. However, whether its hypotensive effect will reduce long-term mortality remains unclear. Our study reported an exploratory follow-up of mortality outcomes from previous randomized controlled trial to assess the long-term effect of low-sodium salt on total and cardiovascular disease (CVD) mortality. Methods: Participants who completed a previous 3-year double-blind randomized controlled trial were followed up from 2009 to 2019 to collect mortality data. Multivariable Cox regression models were used to evaluate the association between low-sodium salt intervention and all-cause and CVD mortality. Results: Four hundred and forty participants completed the intervention trial, of which 428 participants had death outcome data recorded after 10 years follow-up: 209 in a salt substitute group and 219 in a normal salt group. Fifty participants died during follow-up, 25 died due to CVD. No significant differences in relative risks were found for all-cause mortality [HR = 0.81, 95% confidence interval (CI): 0.46-1.42] and CVD mortality (HR = 0.58, 95% CI: 0.26-1.32) in unadjusted analyses. After adjusted with age and alcohol drinking status, there were significant reductions for stroke mortality among all participants (HR = 0.26, 95% CI: 0.08-0.84) and for CVD mortality (HR = 0.38, 95% CI: 0.16-0.92) and stroke mortality (HR = 0.25, 95% CI: 0.08-0.82) among hypertensive participants. Conclusions: Compared to normal salt, salt substitute might reduce the risk of CVD death, especially stroke among hypertensive patients. Our exploratory follow-up results provide potential evidence that low-sodium salt may be an accessible and effective strategy for prevention of CVD events, but definitive randomized controlled trials are warranted.
Keywords: CVD mortality; all-cause mortality; hypertension; salt substitute; stroke mortality.

[AlPater]

The ATP Level in the mPFC Mediates the Antidepressant Effect of Calorie Restriction.
Wang Q, Kong Y, Lin S, Wu DY, Hu J, Huang L, Zang WS, Li XW, Yang JM, Gao TM.
Neurosci Bull. 2021 Jun 5. doi: 10.1007/s12264-021-00726-4. Online ahead of print.
PMID: 34089507
Abstract
Food deprivation can rescue obesity and overweight-induced mood disorders, and promote mood performance in normal subjects. Animal studies and clinical research have revealed the antidepressant-like effect of calorie restriction, but little is known about the mechanism of calorie restriction-induced mood modification. Previous studies have found that astrocytes modulate depressive-like behaviors. Inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is the predominant isoform in mediating astrocyte Ca2+ signals and its genetic knockout mice are widely used to study astrocyte function in vivo. In this study, we showed that deletion of IP3R2 blocked the antidepressant-like effect induced by calorie restriction. In vivo microdialysis experiments demonstrated that calorie restriction induced an increase in ATP level in the medial prefrontal cortex (mPFC) in naïve mice but this effect disappeared in IP3R2-knockout mice, suggesting a role of astrocytic ATP in the calorie restriction-induced antidepressant effect. Further experiments showed that systemic administration and local infusion of ATP into the mPFC induced an antidepressant effect, whereas decreasing ATP by Apyrase in the mPFC blocked calorie restriction-induced antidepressant regulation. Together, these findings support a role for astrocytic ATP in the antidepressant-like effect caused by calorie restriction.
Keywords: ATP; Astrocyte; Calorie restriction; Depression; IP3R2.

[AlPater]

A randomized controlled trial to isolate the effects of fasting and energy restriction on weight loss and metabolic health in lean adults.
Templeman I, Smith HA, Chowdhury E, Chen YC, Carroll H, Johnson-Bonson D, Hengist A, Smith R, Creighton J, Clayton D, Varley I, Karagounis LG, Wilhelmsen A, Tsintzas K, Reeves S, Walhin JP, Gonzalez JT, Thompson D, Betts JA.
Sci Transl Med. 2021 Jun 16;13(598):eabd8034. doi: 10.1126/scitranslmed.abd8034.
PMID: 34135111
Abstract
Intermittent fasting may impart metabolic benefits independent of energy balance by initiating fasting-mediated mechanisms. This randomized controlled trial examined 24-hour fasting with 150% energy intake on alternate days for 3 weeks in lean, healthy individuals (0:150; n = 12). Control groups involved a matched degree of energy restriction applied continuously without fasting (75% energy intake daily; 75:75; n = 12) or a matched pattern of fasting without net energy restriction (200% energy intake on alternate days; 0:200; n = 12). Primary outcomes were body composition, components of energy balance, and postprandial metabolism. Daily energy restriction (75:75) reduced body mass (-1.91 ± 0.99 kilograms) almost entirely due to fat loss (-1.75 ± 0.79 kilograms). Restricting energy intake via fasting (0:150) also decreased body mass (-1.60 ± 1.06 kilograms; P = 0.46 versus 75:75) but with attenuated reductions in body fat (-0.74 ± 1.32 kilograms; P = 0.01 versus 75:75), whereas fasting without energy restriction (0:200) did not significantly reduce either body mass (-0.52 ± 1.09 kilograms; P ≤ 0.04 versus 75:75 and 0:150) or fat mass (-0.12 ± 0.68 kilograms; P ≤ 0.05 versus 75:75 and 0:150). Postprandial indices of cardiometabolic health and gut hormones, along with the expression of key genes in subcutaneous adipose tissue, were not statistically different between groups (P > 0.05). Alternate-day fasting less effectively reduces body fat mass than a matched degree of daily energy restriction and without evidence of fasting-specific effects on metabolic regulation or cardiovascular health.

Calorie restriction conferred improvement effect on long-term rehabilitation of ischemic stroke via gut microbiota.
Huang JT, Mao YQ, Han B, Zhang ZY, Chen HL, Li ZM, Kong CY, Xu JQ, Cai PR, Zeng YP, Zhao J, Zhao YP, Wang LS.
Pharmacol Res. 2021 Jun 11:105726. doi: 10.1016/j.phrs.2021.105726. Online ahead of print.
PMID: 34126228
Abstract
Calorie restriction can modulate the gut microbiota and protect against many diseases including ischemic stroke. However, the role of calorie-restriction-induced microbiota alteration remained unknown in ischemic stroke rehabilitation. Here we conducted 30% reduction of caloric intake on mice for four weeks, to evaluate its role on ischemic stroke rehabilitation. Significantly, this calorie restriction led to better long-term rehabilitation in comparison of normal control. Notably, the transplantation of gut microbiome from calorie-restriction-treated mice to post-stroke mice was eligible to obtain better long-term rehabilitation of stroke mice. Bifidobacterium identified by 16S ribosomal RNA sequencing were enriched in those of calorie-restriction mice. Then we administrated Bifidobacterium to stroke mice and found Bifidobacterium treatment could successfully improve the long-term rehabilitation of cerebral ischemia mice. Furthermore, the metabolomics analysis revealed a panel of upshifting metabolites, suggesting that calorie restriction greatly altered the gut microbiota composition and its metabolism. Hence, we discovered the novel effect of CR on long-term rehabilitation of ischemic stroke and the underlying role of gut microbiota, which might provide novel thoughts for the clinical post-stroke rehabilitation. IN BRIEF: Calorie restriction confers protective effects on long-term rehabilitation of stroke, partly through gut microbiota modulation, especially by enrichment of Bifidobacterium.
Keywords: calorie restriction; gut microbiota; ischemic stroke; rehabilitation.

Caloric restriction enhances vascular tone of cerebral and mesenteric resistance arteries in aged rats.
Tropea T, Mandalà M.
Mech Ageing Dev. 2021 Jun 12:111520. doi: 10.1016/j.mad.2021.111520. Online ahead of print.
PMID: 34129890
Abstract
Vascular changes of tone and biomechanical properties induced by ageing increase the risk for cardiovascular diseases. Caloric restriction (CR) has been shown to protect against cardiovascular diseases and improve endothelial dysfunction in cerebral resistance arteries. We hypothesise that CR will enhance vascular tone and structural properties of cerebral resistance arteries and exert comparable beneficial effects on the systemic vasculature of aged rat model. Eighteen-month-old male Sprague-Dawley rats were feed either ad libitum or restricted to 60% of calorie consumption up to 24 months of age, when body weight (BW) measurements were taken and functional and structural properties of resistance arteries were assessed using a pressure myograph. In cerebral arteries, CR increased myogenic tone (p < 0.001) and distensibility (p < 0.01) in response to intraluminal pressure and concentration-dependent constriction to KCl (p < 0.001). In mesenteric arteries constriction in response to KCl was increased (p < 0.0001) and wall thickness reduced (p < 0.01) in CR rats. BW was reduced (p < 0.0001) in FR rats. Our findings demonstrate that CR improves vascular tone of resistance arteries regardless the type of stimulus and independently of the vascular bed. CR may be a beneficial dietary approach to prevent age-related vascular diseases.
Keywords: Ageing; endothelial cell; smooth muscle cells; vascular structure.

[AlPater]

Effect of 2-year caloric restriction on organ and tissue size in nonobese 21- to 50-year-old adults in a randomized clinical trial: the CALERIE study.
Shen W, Chen J, Zhou J, Martin CK, Ravussin E, Redman LM.
Am J Clin Nutr. 2021 Jun 22:nqab205. doi: 10.1093/ajcn/nqab205. Online ahead of print.
PMID: 34159359
Abstract
Background: Sustained calorie restriction (CR) promises to extend the lifespan. The effect of CR on changes in body mass across tissues and organs is unclear.
Objectives: We used whole-body MRI to evaluate the effect of 2 y of CR on changes in body composition.
Methods: In an ancillary study of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, 43 healthy adults [25-50 y; BMI (kg/m2): 22-28] randomly assigned to 25% CR (n = 28) or ad libitum (AL) eating (n = 15) underwent whole-body MRI at baseline and month 24 to measure adipose tissue in subcutaneous, visceral, and intermuscular depots (SAT, VAT, and IMAT, respectively); skeletal muscle; and organs including brain, liver, spleen, and kidneys but not heart.
Results: The CR group lost more adipose tissue and lean tissue than controls (P < 0.05). In the CR group, at baseline, total tissue volume comprised 32.1%, 1.9%, and 1.0% of SAT, VAT, and IMAT, respectively. The loss of total tissue volume over 24 mo comprised 68.4%, 7.4%, and 2.2% of SAT, VAT, and IMAT, respectively, demonstrating preferential loss of fat vs. lean tissue. Although there is more muscle loss in CR than AL (P < 0.05), the loss of muscle over 24 mo in the CR group comprised only 17.2% of the loss of total tissue volume. Changes in organ volumes were not different between CR and AL. The degree of CR (% decrease in energy intake vs. baseline) significantly (P < 0.05) affected changes in VAT, IMAT, muscle, and liver volume (standardized regression coefficient ± standard error of estimates: 0.43 ± 0.15 L, 0.40 ± 0.19 L, 0.55 ± 0.17 L, and 0.45 ± 0.18 L, respectively).
Conclusions: Twenty-four months of CR (intended, 25%; actual, 13.7%) in young individuals without obesity had effects on body composition, including a preferential loss of adipose tissue, especially VAT, over the loss of muscle and organ tissue.
Keywords: aging; body composition; brain; caloric restriction; magnetic resonance imaging; organ.

The effect of caloric restriction on the increase in senescence-associated T cells and metabolic disorders in aged mice.
Yan X, Imano N, Tamaki K, Sano M, Shinmura K.
PLoS One. 2021 Jun 18;16(6):e0252547. doi: 10.1371/journal.pone.0252547. eCollection 2021.
PMID: 34143796
Abstract
Aging is associated with functional decline in the immune system and increases the risk of chronic diseases owing to smoldering inflammation. In the present study, we demonstrated an age-related increase in the accumulation of Programmed Death-1 (PD-1)+ memory-phenotype T cells that are considered "senescence-associated T cells" in both the visceral adipose tissue and spleen. As caloric restriction is an established intervention scientifically proven to exert anti-aging effects and greatly affects physiological and pathophysiological alterations with advanced age, we evaluated the effect of caloric restriction on the increase in this T-cell subpopulation and glucose tolerance in aged mice. Long-term caloric restriction significantly decreased the number of PD-1+ memory-phenotype cluster of differentiation (CD) 4+ and CD8+ T cells in the spleen and visceral adipose tissue, decreased M1-type macrophage accumulation in visceral adipose tissue, and improved insulin resistance in aged mice. Furthermore, the immunological depletion of PD-1+ T cells reduced adipose inflammation and improved insulin resistance in aged mice. Taken together with our previous report, these results indicate that senescence-related T-cell subpopulations are involved in the development of chronic inflammation and insulin resistance in the context of chronological aging and obesity. Thus, long-term caloric restriction and specific deletion of senescence-related T cells are promising interventions to regulate age-related chronic diseases.

[AlPater]

Caloric restriction disrupts the microbiota and colonization resistance.
von Schwartzenberg RJ, Bisanz JE, Lyalina S, Spanogiannopoulos P, Ang QY, Cai J, Dickmann S, Friedrich M, Liu SY, Collins SL, Ingebrigtsen D, Miller S, Turnbaugh JA, Patterson AD, Pollard KS, Mai K, Spranger J, Turnbaugh PJ.
Nature. 2021 Jun 23. doi: 10.1038/s41586-021-03663-4. Online ahead of print.
PMID: 34163067
Abstract
Diet is a major factor that shapes the gut microbiome1, but the consequences of diet-induced changes in the microbiome for host pathophysiology remain poorly understood. We conducted a randomized human intervention study using a very-low-calorie diet (NCT01105143). Although metabolic health was improved, severe calorie restriction led to a decrease in bacterial abundance and restructuring of the gut microbiome. Transplantation of post-diet microbiota to mice decreased their body weight and adiposity relative to mice that received pre-diet microbiota. Weight loss was associated with impaired nutrient absorption and enrichment in Clostridioides difficile, which was consistent with a decrease in bile acids and was sufficient to replicate metabolic phenotypes in mice in a toxin-dependent manner. These results emphasize the importance of diet–microbiome interactions in modulating host energy balance and the need to understand the role of diet in the interplay between pathogenic and beneficial symbionts.
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NEWS RELEASE 23-JUN-2021
Nature article: Dieting and its effect on the gut microbiome
Bacterium associated with antibiotic-induced colitis plays a role in weight control
https://www.eurekalert.org/pub_releases/2021-06/c-ub-nad062321.php
Researchers from Charité - Universitätsmedizin Berlin and the University of California in San Francisco were able to show for the first time that a very low calorie diet significantly alters the composition of the microbiota present in the human gut. In a current Nature* publication, the researchers report that dieting results in an increase of specific bacteria - notably Clostridioides difficile, which is associated with antibiotic-induced diarrhea and colitis. These bacteria apparently affect the body's energy balance by exerting an influence on the absorption of nutrients from the gut.
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[AlPater]

Chronic food restriction enhances dopamine-mediated intracranial self-stimulation.
Gnazzo FG, Mourra D, Guevara CA, Beeler JA.
Neuroreport. 2021 Jul 19. doi: 10.1097/WNR.0000000000001700. Online ahead of print.
PMID: 34284450
Abstract
Dopamine-mediated reinforcement and behavioral adaptation is essential to survival. Here, we test the effects of food restriction on dopamine-mediated learning and reinforcement using optical intracranial self-stimulation (oICSS), an optogenetic version of conventional electrical ICSS (also known as brain stimulation reward, BSR). Using mouse genetic lines to express channelrhodopsin selectively in midbrain dopamine neurons, we demonstrate that genetically expressed channelrhodopsin can mediate optically evoked dopamine release and support self-stimulation in a lever-pressing paradigm. Using this midbrain dopamine oICSS preparation, we compare acquisition and rate of pressing in ad libitum versus food restricted mice. Food restriction facilitated both more rapid acquisition of self-stimulation behavior and higher rates of responding; reversing food status after acquisition modulated response vigor in already established behavior. These data suggest that food restriction enhances both the acquisition and expression of dopamine-reinforced self-stimulation responding. These data demonstrate the utility of oICSS for examining changes in reinforcement learning concomitant to neuroadaptations induced in dopamine signaling by experimental manipulations such as food restriction.

Caloric restriction inhibits renal artery ageing by reducing endothelin-1 expression.
Wang XH, Ao QG, Cheng QL.
Ann Transl Med. 2021 Jun;9(12):979. doi: 10.21037/atm-21-2218.
PMID: 34277779 Free PMC article.
Abstract
Background: The renal artery plays a central role in renal perfusion and is critical for proper renal function. Ageing is an independent risk factor for both impaired renal function and vascular disorders, and associated with an increase in the expression of the vasoconstrictor endothelin-1 (ET-1), and caloric restriction (CR) without malnutrition has been shown to be an effective inhibitor of renal dysfunction induced by ageing. The objective of this study was to determine whether CR-mediated alleviation of renal dysfunction is mediated by ET-1 expression.
Methods: The young (2 months, 2 M) and old (12 months, 12 M) Sprague-Dawley male rats were used and fed ad libitum. The 12-month-old rats were further divided into 12 M and 12 M-caloric restriction (CR) (30% calorie restriction). After 8 weeks, the renal tissues were showed by PAS staining, and age-related metabolic parameters and renal functions were detected in each group of rats. The inflammatory cytokines of interleukin (IL)-6, IL-1β, tumor necrosis factor alpha (TNF-α), and transforming growth factor beta 1 (TGF-β1) were analyzed using ELISA. The mRNA and protein expression in the renal artery were analysis by qRT-PCR and Immunoblot analysis.
Results: Ageing was associated with significant increases in 24 h urine protein content and serum triglyceride and cholesterol in 12 M rats, both of which were significantly inhibited in 12 M-CR. The mRNA expression and the secretion of IL-6, IL-1β, TNF-α, and TGF-β1 in the renal artery was significantly increased with ageing and inhibited by CR. CR also inhibited ageing-induced Edn1 (encoding ET-1) mRNA and protein expression in the renal artery. In addition, CR could regulate ET-1 expression by inhibiting the activation of NF-κB signaling and activation and induction in the expression of NF-E2-related factor 2 (Nrf2) and histone deacetylase and gene repressor sirtuin 1 (SIRT1), both of which play a central role in mitigating oxidative stress in young rats.
Conclusions: Moderate CR can reverse the ageing related kidney dysfunction by reducing the ET-1 expression. CR might be used as an alternative to prevent the ageing induced renal artery dysfunction.
Keywords: Caloric restriction (CR); NF-κB signaling; ageing; endothelin-1 (ET-1); renal artery.

[AlPater]

Caloric restriction alleviates radiation injuries in a sex-dependent fashion.
Li Y, Dong J, Xiao H, Wang B, Chen Z, Zhang S, Jin Y, Li Y, Fan S, Cui M.
FASEB J. 2021 Aug;35(8):e21787. doi: 10.1096/fj.202100351RR.
PMID: 34320242
Abstract
Safe and effective regimens are still needed given the risk of radiation toxicity from iatrogenic irradiation. The gut microbiota plays an important role in radiation damage. Diet has emerged as a key determinant of the intestinal microbiome signature and function. In this report, we investigated whether a 30% caloric restriction (CR) diet may ameliorate radiation enteritis and hematopoietic toxicity. Experimental mice were either fed ad libitum (AL) or subjected to CR preconditioning for 10 days and then exposed to total body irradiation (TBI) or total abdominal irradiation (TAI). Gross examinations showed that short-term CR pretreatment restored hematogenic organs and improved the intestinal architecture in both male and female mice. Intriguingly, CR preconditioning mitigated radiation-induced systemic and enteric inflammation in female mice, while gut barrier function improved in irradiated males. 16S rRNA high-throughput sequencing showed that the frequency of pro-inflammatory microbes, including Helicobacter and Desulfovibrionaceae, was reduced in female mice after 10 days of CR preconditioning, while an enrichment of short-chain fatty acid (SCFA)-producing bacteria, such as Faecalibaculum, Clostridiales, and Lactobacillus, was observed in males. Using fecal microbiota transplantation (FMT) or antibiotic administration to alter the gut microbiota counteracted the short-term CR-elicited radiation tolerance of both male and female mice, further indicating that the radioprotection of a 30% CR diet depends on altering the gut microbiota. Together, our findings provide new insights into CR in clinical applications and indicate that a short-term CR diet prior to radiation modulates sex-specific gut microbiota configurations, protecting male and female mice against the side effects caused by radiation challenge.
Keywords: caloric restriction; intestinal microbiota; radiation injury; sex-specific.

[AlPater]

The effects of graded calorie restriction XVII: Multitissue metabolomics reveals synthesis of carnitine and NAD, and tRNA charging as key pathways.
García-Flores LA, Green CL, Mitchell SE, Promislow DEL, Lusseau D, Douglas A, Speakman JR.
Proc Natl Acad Sci U S A. 2021 Aug 3;118(31):e2101977118. doi: 10.1073/pnas.2101977118.
PMID: 34330829
Abstract
The evolutionary context of why caloric restriction (CR) activates physiological mechanisms that slow the process of aging remains unclear. The main goal of this analysis was to identify, using metabolomics, the common pathways that are modulated across multiple tissues (brown adipose tissue, liver, plasma, and brain) to evaluate two alternative evolutionary models: the "disposable soma" and "clean cupboards" ideas. Across the four tissues, we identified more than 10,000 different metabolic features. CR altered the metabolome in a graded fashion. More restriction led to more changes. Most changes, however, were tissue specific, and in some cases, metabolites changed in opposite directions in different tissues. Only 38 common metabolic features responded to restriction in the same way across all four tissues. Fifty percent of the common altered metabolites were carboxylic acids and derivatives, as well as lipids and lipid-like molecules. The top five modulated canonical pathways were l-carnitine biosynthesis, NAD (nicotinamide adenine dinucleotide) biosynthesis from 2-amino-3-carboxymuconate semialdehyde, S-methyl-5'-thioadenosine degradation II, NAD biosynthesis II (from tryptophan), and transfer RNA (tRNA) charging. Although some pathways were modulated in common across tissues, none of these reflected somatic protection, and each tissue invoked its own idiosyncratic modulation of pathways to cope with the reduction in incoming energy. Consequently, this study provides greater support for the clean cupboards hypothesis than the disposable soma interpretation.

[JP223322]

Very interesting.

it would be best if you could reply with the URL’s from the studies. (IBooks import)

after dropping 60lb in 6 months, I’ve friend my attention to longevity amd Epigenetics.

Specifically using  CR to trigger Apoptosis (re: Valta Longo).

Seems to me that triglyceride levels should be a good indicator that the conditions are right for Apoptosis, if I’ve read the studies, Triglycerides increase if extra calories need to be transported to cells.

Mine have been around 46 for 4 months (when I finally moved to a WFPB life style).

Too many studies posted here .. the links would have been a better approach .. a case of “can’t see the wood for the trees”.

 

 

[AlPater]

Protective Features of Calorie Restriction on Cuprizone-induced Demyelination via Modulating Microglial Phenotype.
Zarini D, Pasbakhsh P, Nekoonam S, Mojaverrostami S, Ghasemi S, Shabani M, Kashani IR.
J Chem Neuroanat. 2021 Aug 12:102013. doi: 10.1016/j.jchemneu.2021.102013. Online ahead of print.
PMID: 34391881
Abstract
Multiple sclerosis (MS) is an immune-mediated demyelinating disorder in the central nervous system (CNS) with no definitive treatment, but it can be alleviated by changing life habits. Calorie restriction (CR) is effective in preventing or treating metabolic and autoimmune disorders. CR is one of the helpful approaches to control the progression of MS. In the present study, we investigated the preventive effect of caloric restriction on cuprizone induced-demyelination, a model of multiple sclerosis. To induce acute demyelination in C57/BL6 mice, we added 0.2% Cuprizone (CPZ) to their diet for 6 weeks. To induce calorie restriction, 10% Carboxymethyl cellulose (CMC) was added to the diet as a dietary cellulose fiber for 6 weeks. Remyelination was studied by luxol fast blue (LFB) staining. Microglia activity, M1 and M2 microglial/macrophage phenotypes were assessed by immunohistochemistry of Iba-1, iNOS and Arg-1, respectively. The expression of targeted genes was assessed by the real-time polymerase chain reaction. Luxol fast blue (LFB) staining showed that the CR regimen could decrease the cuprizone-induced demyelination process (p < 0.01). Moreover, the CR application could improve balance and motor performance in cuprizone-intoxicated mice by significantly enhancing protein and gene expression of Sirt1, M2 microglial phenotype marker (Arg-1) and Akt1 gene expression, also decreased M1 microglial phenotype marker (iNOS), Akt2 and P53 gene expressions (p < 0.05). Cumulatively, it can be concluded that caloric restriction was able to counteract MS symptoms through alleviating inflammatory responses.
Keywords: Calorie restriction; Cuprizone; Demyelination; Microglia; Multiple Sclerosis.

Lamin regulates the dietary restriction response via the mTOR pathway in Caenorhabditis elegans.
Charar C, Metsuyanim-Cohen S, Bar DZ.
J Cell Sci. 2021 Aug 12:jcs.258428. doi: 10.1242/jcs.258428. Online ahead of print.
PMID: 34383046
Abstract
Animals subjected to dietary restriction (DR) have reduced body size, low fecundity, slower development, lower fat content and longer life span. We identified lamin as a regulator of multiple dietary restriction phenotypes. Downregulation of lmn-1, the single Caenorhabditis elegans lamin gene, increased animal size and fat content, specifically in DR animals. The LMN-1 protein acts in the mTOR pathway, upstream to RAPTOR and S6K, key component and target of mTOR complex 1 (mTORC1), respectively. DR excludes the mTORC1 activator RAGC-1 from the nucleus. Downregulation of lmn-1 restores RAGC-1 to the nucleus, a necessary step for the activation of the mTOR pathway. These findings further link lamin to metabolic regulation.
Keywords: Caenorhabditis elegans; Dietary restriction; Lamin; mTOR.

[AlanPater]

The impact of low-protein high-carbohydrate diets on aging and lifespan.
Le Couteur DG, Solon-Biet S, Cogger VC, Mitchell SJ, Senior A, de Cabo R, Raubenheimer D, Simpson SJ.
Cell Mol Life Sci. 2016 Mar;73(6):1237-52. doi: 10.1007/s00018-015-2120-y. Epub 2015 Dec 30.
PMID: 26718486 Review.
Abstract
Most research on nutritional effects on aging has focussed on the impact of manipulating single dietary factors such as total calorie intake or each of the macronutrients individually. More recent studies using a nutritional geometric approach called the Geometric Framework have facilitated an understanding of how aging is influenced across a landscape of diets that vary orthogonally in macronutrient and total energy content. Such studies have been performed using ad libitum feeding regimes, thus taking into account compensatory feeding responses that are inevitable in a non-constrained environment. Geometric Framework studies on insects and mice have revealed that diets low in protein and high in carbohydrates generate longest lifespans in ad libitum-fed animals while low total energy intake (caloric restriction by dietary dilution) has minimal effect. These conclusions are supported indirectly by observational studies in humans and a heterogeneous group of other types of interventional studies in insects and rodents. Due to compensatory feeding for protein dilution, low-protein, high-carbohydrate diets are often associated with increased food intake and body fat, a phenomenon called protein leverage. This could potentially be mitigated by supplementing these diets with interventions that influence body weight through physical activity and ambient temperature.
Keywords: Ageing; Aging; CPC diet; Caloric restriction; Dietary carbohydrate; Dietary protein; Geometric Framework.

"Calories in, calories out" and macronutrient intake: the hope, hype, and science of calories.
Howell S, Kones R.
Am J Physiol Endocrinol Metab. 2017 Nov 1;313(5):E608-E612. doi: 10.1152/ajpendo.00156.2017. Epub 2017 Aug 1.
PMID: 28765272 Free article.
Abstract
One of the central tenets in obesity prevention and management is caloric restriction. This perspective presents salient features of how calories and energy balance matter, also called the "calories in, calories out" paradigm. Determinants of energy balance and relationships to dietary macronutrient content are reviewed. The rationale and features of the carbohydrate-insulin hypothesis postulate that carbohydrate restriction confers a metabolic advantage. According to this model, a large amount of fat intake is enabled without weight gain. Evidence concerning this possibility is detailed. The relationship and application of the laws of thermodynamics are then clarified with current primary research. Strong data indicate that energy balance is not materially changed during isocaloric substitution of dietary fats for carbohydrates. Results from a number of sources refute both the theory and effectiveness of the carbohydrate-insulin hypothesis. Instead, risk for obesity is primarily determined by total calorie intake.
Keywords: CHO-insulin hypothesis; NuSI; calories in, calories out; energy expenditure; laws of thermodynamics; low-carbohydrate diet; metabolic adaptation; metabolic advantage; obesity; thermic effect of food.

[AlanPater]

The impact of low-protein high-carbohydrate diets on aging and lifespan.
Le Couteur DG, Solon-Biet S, Cogger VC, Mitchell SJ, Senior A, de Cabo R, Raubenheimer D, Simpson SJ.
Cell Mol Life Sci. 2016 Mar;73(6):1237-52. doi: 10.1007/s00018-015-2120-y. Epub 2015 Dec 30.
PMID: 26718486 Review.
Abstract
Most research on nutritional effects on aging has focussed on the impact of manipulating single dietary factors such as total calorie intake or each of the macronutrients individually. More recent studies using a nutritional geometric approach called the Geometric Framework have facilitated an understanding of how aging is influenced across a landscape of diets that vary orthogonally in macronutrient and total energy content. Such studies have been performed using ad libitum feeding regimes, thus taking into account compensatory feeding responses that are inevitable in a non-constrained environment. Geometric Framework studies on insects and mice have revealed that diets low in protein and high in carbohydrates generate longest lifespans in ad libitum-fed animals while low total energy intake (caloric restriction by dietary dilution) has minimal effect. These conclusions are supported indirectly by observational studies in humans and a heterogeneous group of other types of interventional studies in insects and rodents. Due to compensatory feeding for protein dilution, low-protein, high-carbohydrate diets are often associated with increased food intake and body fat, a phenomenon called protein leverage. This could potentially be mitigated by supplementing these diets with interventions that influence body weight through physical activity and ambient temperature.

[AlanPater]

Calorie restriction improves lipid-related emerging cardiometabolic risk factors in healthy adults without obesity: Distinct influences of BMI and sex from CALERIE™ a multicentre, phase 2, randomised controlled trial.
Huffman KM, et al.
EClinicalMedicine. 2022.
PMID: 35028547 Free PMC article.
Abstract
Background: For many cardiovascular risk factors there is no lower limit to which further reduction will result in decreased disease risk; this includes values within ranges considered normal for healthy adults. This seems to be true for new emerging metabolic risk factors identified by innovative technological advances. Further, there seems to be ever evolving evidence of differential responses to lifestyle interventions by sex and body compositions in the normal range. In this secondary analysis, we had the opportunity to test these principles for newly identified molecular biomarkers of cardiometabolic risk in a young (21-50 years), normal weight healthy population undergoing calorie restriction for two years.
Methods: The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) was a 24-month, multicenter, randomized controlled trial (May 2007-November 2012) in healthy, adults without obesity to evaluate the potential for calorie restriction (CR) to promote anti-aging adaptations, including those associated with disease risk. 218 participants (age 37.9 ± 7.2 years and body mass index (BMI) 25.1 ± 1.7 kg/m2, mean±SD) were randomized 2:1 to 24 months of CR (prescribed as 25% reduction from baseline calorie intake) versus ad libitum (AL). Fasting plasma from baseline, 12, and 24 months was used for assessments of lipoproteins, metabolites, and inflammatory markers using nuclear magnetic resonance spectroscopy.
Findings: Averaging 11.9% CR, the CR group had reductions at 12 and 24 months in the cardiovascular disease risk markers, apolipoprotein B and GlycA, and risks for insulin resistance and type 2 diabetes-Lipoprotein Insulin Resistance Index and Diabetes Risk Index (all PCRvsAL ≤0.0009). Insulin resistance and diabetes risk improvements resulted from CR-induced alterations in lipoproteins, specifically reductions in triglyceride-rich lipoprotein particles and low-density lipoprotein particles, a shift to larger high-density lipoprotein particles (more effective cholesterol transporters), and reductions in branched chain amino acids (BCAAs) (all PCRvsAL ≤0.004). These CR responses were more pronounced in overweight than normal weight participants and greater in men than women.
Interpretation: In normal to slightly overweight adults without overt risk factors or disease, 12 months of ∼12% CR improved newly identified risk markers for atherosclerotic cardiovascular disease, insulin resistance and type 2 diabetes. These markers suggest that CR improves risks by reducing inflammation and BCAAs and shifting lipoproteins from atherogenic to cholesterol transporting. Additionally, these improvements are greater for men and for those with greater BMIs indicating sex and BMI-influences merit attention in future investigations of lifestyle-mediated improvements in disease risk factors.
Keywords: Cardiovascular disease; Insulin resistance; Nuclear magnetic resonance spectroscopy; Type 2 diabetes risk.

The impact of low-protein high-carbohydrate diets on aging and lifespan.
Le Couteur DG, Solon-Biet S, Cogger VC, Mitchell SJ, Senior A, de Cabo R, Raubenheimer D, Simpson SJ.
Cell Mol Life Sci. 2016 Mar;73(6):1237-52. doi: 10.1007/s00018-015-2120-y. Epub 2015 Dec 30.
PMID: 26718486 Review.
https://sci-hub.se/
Abstract
Most research on nutritional effects on aging has focussed on the impact of manipulating single dietary factors such as total calorie intake or each of the macronutrients individually. More recent studies using a nutritional geometric approach called the Geometric Framework have facilitated an understanding of how aging is influenced across a landscape of diets that vary orthogonally in macronutrient and total energy content. Such studies have been performed using ad libitum feeding regimes, thus taking into account compensatory feeding responses that are inevitable in a non-constrained environment. Geometric Framework studies on insects and mice have revealed that diets low in protein and high in carbohydrates generate longest lifespans in ad libitum-fed animals while low total energy intake (caloric restriction by dietary dilution) has minimal effect. These conclusions are supported indirectly by observational studies in humans and a heterogeneous group of other types of interventional studies in insects and rodents. Due to compensatory feeding for protein dilution, low-protein, high-carbohydrate diets are often associated with increased food intake and body fat, a phenomenon called protein leverage. This could potentially be mitigated by supplementing these diets with interventions that influence body weight through physical activity and ambient temperature.
Keywords: Ageing; Aging; CPC diet; Caloric restriction; Dietary carbohydrate; Dietary protein; Geometric Framework.

Nutrition and energetics in rodent longevity research.
Gibbs VK, Smith DL Jr.
Exp Gerontol. 2016 Dec 15;86:90-96. doi: 10.1016/j.exger.2016.04.004. Epub 2016 Apr 9.
PMID: 27073168 Free PMC article. Review.
Abstract
The impact of calorie amount on aging has been extensively described; however, variation over time and among laboratories in animal diet, housing condition, and strains complicates discerning the true influence of calories (energy) versus nutrients on lifespan. Within the dietary restriction field, single macronutrient manipulations have historically been researched as a means to reduce calories while maintaining adequate levels of essential nutrients. Recent reports of nutritional geometry, including rodent models, highlight the impact macronutrients have on whole organismal aging outcomes. However, other environmental factors (e.g., ambient temperature) may alter nutrient preferences and requirements revealing context specific outcomes. Herein we highlight factors that influence the energetic and nutrient demands of organisms which oftentimes have underappreciated impacts on clarifying interventional effects on health and longevity in aging studies and subsequent translation to improve the human condition.
Keywords: Carbohydrate; Dietary restriction; Longevity; Macronutrients; Protein; Thermogenesis.

[AlanPater]

Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice.
Acosta-Rodríguez V, Rijo-Ferreira F, Izumo M, Xu P, Wight-Carter M, Green CB, Takahashi JS.
Science. 2022 May 5:e. doi: 10.1126/science.abk0297. Online ahead of print.
PMID: 35511946
Abstract
Caloric restriction (CR) prolongs lifespan, yet the mechanisms by which it does so remain poorly understood. Under CR, mice self-impose chronic cycles of 2-hour-feeding and 22-hour-fasting, raising the question whether calories, fasting, or time of day are causal. We show that 30%-CR is sufficient to extend lifespan 10%; however, a daily fasting interval and circadian-alignment of feeding act together to extend lifespan 35% in male C57BL/6J mice. These effects are independent of body weight. Aging induces widespread increases in gene expression associated with inflammation and decreases in expression of genes encoding components of metabolic pathways in liver from ad lib fed mice. CR at night ameliorates these aging-related changes. Thus, circadian interventions promote longevity and provide a perspective to further explore mechanisms of aging.

[AlanPater]

Caloric restriction in humans reveals immunometabolic regulators of health span.
Spadaro O, Youm Y, Shchukina I, Ryu S, Sidorov S, Ravussin A, Nguyen K, Aladyeva E, Predeus AN, Smith SR, Ravussin E, Galban C, Artyomov MN, Dixit VD.
Science. 2022 Feb 11;375(6581):671-677. doi: 10.1126/science.abg7292. Epub 2022 Feb 10.
PMID: 35143297
Abstract
The extension of life span driven by 40% caloric restriction (CR) in rodents causes trade-offs in growth, reproduction, and immune defense that make it difficult to identify therapeutically relevant CR-mimetic targets. We report that about 14% CR for 2 years in healthy humans improved thymopoiesis and was correlated with mobilization of intrathymic ectopic lipid. CR-induced transcriptional reprogramming in adipose tissue implicated pathways regulating mitochondrial bioenergetics, anti-inflammatory responses, and longevity. Expression of the gene Pla2g7 encoding platelet activating factor acetyl hydrolase (PLA2G7) is inhibited in humans undergoing CR. Deletion of Pla2g7 in mice showed decreased thymic lipoatrophy, protection against age-related inflammation, lowered NLRP3 inflammasome activation, and improved metabolic health. Therefore, the reduction of PLA2G7 may mediate the immunometabolic effects of CR and could potentially be harnessed to lower inflammation and extend the health span.