Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Little is known regarding the long-term effects of caloric restriction (CR) on the risk for atherosclerosis. We evaluated the effect of CR on risk factors for atherosclerosis in individuals who are restricting food intake to slow aging. We studied 18 individuals who had been on CR for an average of 6 years and 18 age-matched healthy individuals on typical American diets. We measured serum lipids and lipoproteins, fasting plasma glucose and insulin, blood pressure (BP), high-sensitivity C-reactive protein (CRP), platelet-derived growth factor AB (PDGF-AB), body composition, and carotid artery intima-media thickness (IMT). The CR group were leaner than the comparison group (body mass index, 19.6 +/- 1.9 vs. 25.9 +/- 3.2 kg/m(2); percent body fat, 8.7 +/- 7% vs. 24 +/- 8%). Serum total cholesterol (Tchol), low-density lipoprotein cholesterol, ratio of Tchol to high-density lipoprotein cholesterol (HDL-C), triglycerides, fasting glucose, fasting insulin, CRP, PDFG-AB, and systolic and diastolic BP were all markedly lower, whereas HDL-C was higher, in the CR than in the American diet group. Medical records indicated that the CR group had serum lipid-lipoprotein and BP levels in the usual range for individuals on typical American diets, and similar to those of the comparison group, before they began CR. Carotid artery IMT was approximately 40% less in the CR group than in the comparison group. Based on a range of risk factors, it appears that long-term CR has a powerful protective effect against atherosclerosis. This interpretation is supported by the finding of a low carotid artery IMT.

Intermittent versus on-demand use of a very low calorie diet: a randomized 2-year clinical trial.
J Intern Med. 2003 Apr;253(4):463-71
Lantz H, Peltonen M, Agren L, Torgerson JS.
Department of Body Composition and Metabolism, Sahlgrenska University Hospital, Goteborg, Sweden. 

To compare two different very low calorie diet (VLCD)-based weight maintenance strategies. DESIGN AND SETTING: A randomized 2-year clinical trial performed at the Department of Body Composition and Metabolism, Sahlgrenska University Hospital, Sweden. SUBJECTS: A total of 334 patients, body mass index (BMI) >30 kg m-2, aged 18-60 years. INTERVENTIONS: All the patients started with 16 VLCD weeks. Subjects in the intermittent group were then scheduled to use VLCD for 2 weeks every third month, whilst patients in the on-demand group were instructed to use VLCD whenever their body weight passed an individualized cut-off level. Irrespective of the treatment group, all the subjects were recommended a hypocaloric diet during VLCD-free periods. MAIN OUTCOME MEASURES: Changes in body weight, body composition, anthropometric variables and cardiovascular risk factors. RESULTS: Completers in both groups maintained highly significant weight losses after 2 years: 7.0 +/- 11.0 kg (6.2 +/- 9.5%) in the intermittent group and 9.1 +/- 9.7 kg (7.7 +/- 8.1%) in the on-demand group (P < 0.001, ns between groups). Male completers in the on-demand group lost significantly more weight than men in the intermittent group, 14.5 +/- 11.0 kg vs. 4.0 +/- 10.5 kg, respectively (P < 0.01). Most cardiovascular risk factors improved during the first year, whilst anthropometric measures, insulin, HDL- and LDL-cholesterol were also significantly improved after 2 years of treatment. CONCLUSION: Clinically significant weight reductions were achieved after 2 years of VLCD-based treatment. The structure of VLCD treatment during the maintenance phase did not affect weight loss in the total study population, whilst male subjects might benefit from the VLCD on-demand strategy.

A randomized trial comparing a very low carbohydrate diet and a calorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy womeny.
J Clin Endocrinol Metab. 2003 Apr;88(4):1617-23 
Brehm BJ, Seeley RJ, Daniels SR, D'Alessio DA. 
University of Cincinnati and Children's Hospital Medical Center, Cincinnati, Ohio 45221-0038, USA.

Untested alternative weight loss diets, such as very low carbohydrate diets, have unsubstantiated efficacy and the potential to adversely affect cardiovascular risk factors. Therefore, we designed a randomized, controlled trial to determine the effects of a very low carbohydrate diet on body composition and cardiovascular risk factors. Subjects were randomized to 6 months of either an ad libitum very low carbohydrate diet or a calorie-restricted diet with 30% of the calories as fat. Anthropometric and metabolic measures were assessed at baseline, 3 months, and 6 months. Fifty-three healthy, obese female volunteers (mean body mass index, 33.6 +/- 0.3 kg/m(2)) were randomized; 42 (79%) completed the trial. Women on both diets reduced calorie consumption by comparable amounts at 3 and 6 months. The very low carbohydrate diet group lost more weight (8.5 +/- 1.0 vs. 3.9 +/- 1.0 kg; P < 0.001) and more body fat (4.8 +/- 0.67 vs. 2.0 +/- 0.75 kg; P < 0.01) than the low fat diet group. Mean levels of blood pressure, lipids, fasting glucose, and insulin were within normal ranges in both groups at baseline. Although all of these parameters improved over the course of the study, there were no differences observed between the two diet groups at 3 or 6 months. beta- Hydroxybutyrate increased significantly in the very low carbohydrate group at 3 months (P = 0.001). Based on these data, a very low carbohydrate diet is more effective than a low fat diet for short-term weight loss and, over 6 months, is not associated with deleterious effects on important cardiovascular risk factors in healthy women.

VLCD-induced weight loss improves heart rate variability in moderately obese Japanese.
CExp Biol Med (Maywood) 2001 May;226(5):440-5
Akehi Y, Yoshimatsu H, Kurokawa M, Sakata T, Eto H, Ito S, Ono J.
Laboratory Medicine, School of Medicine, Fukuoka University, Japan. 

To evaluate the effects of weight reduction on the autonomic nervous system in obese patients, we investigated heart rate variability (HRV) based on 24-hr ambulatory electrocardiogram (ECG) recordings before and after weight reduction. To aim for weight reduction, 16 obese patients were treated with the very-low-calorie conventional Japanese diet (VLCD-CJ) therapy combined with behavior therapy. Percent weight reduction was 17.8% +/- 1.5% (means +/- SEM), but mean blood pressure did not change significantly after VLCD-CJ therapy. The mean normal R-R interval (mNN) of the 24-hr ECG and all other five time-domain indices increased after weight reduction. Spectral analysis revealed that weight reduction increased the high frequency (HF) component, but decreased the ratio of low to high (LF/HF) components. Rate of change in mNN or HF correlated positively with reduction rate of body mass index, but not that in LF/HF. Analysis of daily fluctuations in each HRV parameter showed that significant improvement after weight loss occurred mainly during the nocturnal period, but an HF component was improved throughout the day and night periods. These findings indicate that functional impairment of the autonomic nervous system in obese subjects, particularly in the nocturnal period, is improved by effective weight reduction after VLCD-CJ therapy.

Calorie restriction attenuates inflammatory responses to myocardial ischemia-reperfusion injury.
Am J Physiol Heart Circ Physiol 2001 May;280(5):H2094-102
Colcombe SJ, Erickson KI, Raz N, Webb AG, Cohen NJ, McAuley E, Kramer AF.
Division of Cardiology, University of Texas Health Science Center, San Antonio, 78229-3900, Texas, USA.

The life-prolonging effects of calorie restriction (CR) may be due to reduced damage from cumulative oxidative stress. Our goal was to determine the long-term effects of moderate dietary CR on the myocardial response to reperfusion after a single episode of sublethal ischemia. Male Fisher 344 rats were fed either an ad libitum (AL) or CR (40% less calories) diet. At age 12 mo the animals were anaesthetized and subjected to thoracotomy and a 15-min left-anterior descending coronary artery occlusion. The hearts were reperfused for various periods. GSH and GSSG levels, nuclear factor-kappaB (NF-kappaB) DNA binding activity, cytokine, and antioxidant enzyme _expression were assessed in the ischemic zones. Sham-operated animals served as controls. Compared with the AL diet, chronic CR limited oxidative stress as seen by rapid recovery in GSH levels in previously ischemic myocardium. CR reduced DNA binding activity of NF-kappaB. The kappaB-responsive cytokines interleukin-1beta and tumor necrosis factor-alpha were transiently expressed in the CR group but persisted longer in the AL group. Furthermore, _expression of manganese superoxide dismutase, a key antioxidant enzyme, was significantly delayed in the AL group. Collectively these data indicate that CR significantly attenuates myocardial oxidative stress and the postischemic inflammatory response.

Weight loss with very-low-calorie diet and cardiovascular risk factors in moderately obese women: one-year follow-up study including ambulatory blood pressure monitoring.
Int J Obes Relat Metab Disord 1998 Jul;22(7):661-6 
Pekkarinen T; Takala I; Mustajoki P. Department of Medicine, Helsinki University Hospital, Finland.

The beneficial effects of weight loss with a very-low-calorie diet (VLCD) on cardiovascular risk factors have been reported at the end of energy restriction. As the effects, especially on blood pressure, may not remain constant during weight maintenance, we studied the longer-term effects of weight loss on 24h ambulatory blood pressure (ABP), lipids, glucose and insulin. DESIGN: Prospective study of a 17-week weight loss programme containing an eight-week VLCD period and follow-up visit at one-year. SUBJECTS: Twenty-nine moderately obese, normotensive or mildly hypertensive women. The mean +/- s.d. body mass index (BMI) was 36.0 +/- 2.6 kg/m2 and mean age 40.3 +/- 8.3 y. RESULTS: In the last week of the VLCD, the mean (s.d.) weight loss was 12.4 +/- 3.3 kg (P < 0.001), at the end of the programme 15.1 +/- 4.4 kg (P < 0.001 vs baseline), and at one-year follow-up 10.7 +/- 7.6 kg (P < 0.001 vs baseline). Mean 24 h ABP decreased 8.0/4.6 mmHg (P < 0.001 for both) on the last week of the VLCD, at the end of the programme, the systolic ABP decrease was 4.7 mmHg (P < 0.01 vs baseline) and diastolic 2.1 mmHg (not statistically significant (NS) vs baseline). At one-year follow-up, the mean systolic ABP decrease was 4.1 mmHg (P < 0.01 vs baseline) and mean diastolic 3.0 mmHg (P < 0.05 vs baseline). Sodium excretion decreased 55 mmol/24 h in the last VLCD week (P < 0.01) and returned to baseline after that. At the one-year follow-up, beneficial changes, compared with baseline, were observed in mean serum glucose (-0.28 mmol/l, P < 0.05), triglyceride (-0.35 mmol/l, P < 0.01) and HDL cholesterol (+0.16 mmol/l, P < 0.001). CONCLUSIONS: This weight loss programme with a VLCD enabled obese subjects to lose weight and decrease cardiovascular risks. Despite some regain in weight during follow-up, the beneficial effects were overall maintained over the year. Sodium intake tended to increase during follow-up. Information on sodium restriction should be included in weight loss programmes.

Modified fasting in treatment of obesity. Effects on serum lipids, electrolytes, liver enzymes, and blood pressure.
Postgrad Med. 1986 Mar; 79(4): 263-7
Valenta LJ, Elias AN

We studied 71 patients who followed a supplemental fasting regimen (Optifast) for up to six weeks. Serum triglyceride levels were lowered significantly. The mean serum cholesterol concentration fell to less than 200 mg/dl after four weeks on the diet, and the high-density lipoprotein/cholesterol ratio increased. Serum glucose and uric acid concentrations, which changed initially, returned to baseline after the third week. Minimal elevation of SGPT concentration was the only change revealed by liver function tests. In general, the patients were hypertensive, and their blood pressure levels were significantly lower after fasting. Our data suggest that supplemental fasting deserves further study as a method of weight loss in obese persons. A majority of the problems that can accompany total starvation and surgical approaches are avoided. Combined with behavior modification techniques and medical supervision, supplemental fasting is an effective initial approach to managing obese patients.

Vegetarian fasting of obese patients: a clinical and biochemical evaluation.
Scand J Gastroenterol. 1982 Apr;17(3):417-24.
Sorbris R, Aly KO, Nilsson-Ehle P, Petersson BG, Ockerman PA.

The effects of vegetarian fasting were evaluated in 14 grossly obese patients who participated in a program comprising 5 weeks' fasting in a lactovegetarian health center. Before and after the fasting period the patients were hospitalized and put on a standardized weight-maintaining diet; at the health center they consumed vegetable juices containing less than 1 MJ and 3 g of protein per day. The weight reduction (mean +/- S.D.) was 13.4 +/- 5.0 kg (from 132.0 +/- 27.2 to 118.6 +/- 16.1 kg). Except for the first few days the patients had no severe hunger sensations. No severe adverse clinical effects were noted. The laboratory status--comprising serum or plasma levels of minerals, protein, and lipids; hematological data; and variables reflecting liver and thyroid function--revealed abnormal group mean values only for ferritin and the acute-phase reactants haptoglobin, C-reactive protein, and anti-chymotrypsin in the obese. The levels of potassium, retinol-binding protein, and haptoglobin decreased, and aminotransferase and lactate dehydrogenase activities and free fatty acid and glycerol concentrations increased as a result of the fasting. The most striking effect of the weight reduction was an increase in the HDL cholesterol levels. Fasting according to the described regimen thus seems to provide a safe method for treatment of obese patients.

Effect of complete fasting on the coagulative and antioxidative properties of blood
Vopr Pitan. 1984 Jul-Aug;(4):20-3.
Muliar LA, Mishchenko VP, Loban' GA, Goncharenko LL, Bobyrev VN.

The effect of 3- and 5-day fasting on coagulation blood properties, antioxidant system activity, and the content of oxidized hemoglobin was studied in 2 series of observations over 22 normal volunteers. Fasting was discovered to lead to the reduction of blood plasma and red cell coagulation, to the deterioration of platelet aggregation, rise in the oxidized hemoglobin content, and to the increase in red cell resistance to peroxide hemolysis. The changes revealed were shown to favour the maintenance of the blood in a liquid state, to lower the risk of intravascular coagulation and thrombus formation.

Metabolic hazards of fasting
T Lawlor, and DG Wells Am
Am J Clin Nutr. 1969 Aug;22(8):1142-9

Increased fibrinolysis during fasting may account for the dramatic improvement and feeling of well-being in patients suffering from thrombophlebitis (caused by clots in the blood vessels in the legs) who are fasting to treat obesity.

Fasting and non-fasting fibrinolytic activity.
Lab Pract. 1967 Apr;16(4):469-70.
Menon IS.

Effect of fasting on fibrinolysis and blood coagulation.
Am J Cardiol. 1962 Oct;10:532-4.
Miettinen M.