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PERIODICAL FASTING AND CALORIC RESTRICTION FOR LIFE EXTENSION, DISEASE TREATMENT AND CREATIVITY.
(clinical and experimental data)
 
 3.4 MECHANISM: HOW DOES CALORIE RESTRICTION RETARD AGING ANDF BOOST HEALTH? 
   
   
  LOWERING OF THE RATE OF GENE DAMAGE  
   
 
Lessons learned from gene expression profile studies of aging and caloric restriction.
Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction.
Aging: gene silencing or gene activation?
Temporal linkage between the phenotypic and genomic responses to caloric restriction.
Effects of caloric restriction on mitochondrial function and gene transcripts in rat muscle.
Caloric restriction and genomic stability.
 
   
   
Ageing Res Rev. 2005 Jan;4(1):55-65.
Lessons learned from gene expression profile studies of aging and caloric restriction.
Park SK, Prolla TA.
Department of Genetics and Medical Genetics, University of Wisconsin, 5302B Genetics building, 445 Henry Mall, Madison, WI 53706, USA.

To examine molecular events associated with aging and its retardation by caloric restriction (CR), we have employed high-density oligonucleotide microarrays to define transcriptional patterns in mouse tissues, including skeletal muscle, brain, heart, and adipose. Aging results in a differential gene expression pattern specific to each tissue, and most alterations can be completely or partially prevented by CR. Transcriptional patterns of tissues from calorie-restricted animals suggest that CR retards the aging process by reducing endogenous damage and by inducing metabolic shifts associated with specific transcriptional profiles. These studies demonstrate that DNA microarrays can be used in aging research to generate panels of hundreds of transcriptional biomarkers, providing a new tool to measure biological age on a tissue-specific basis and to evaluate interventions designed to mimic the effects of CR.

   
   
Mech Ageing Dev. 2005 May 28.
Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction.
Spindler SR.
Department of Biochemistry, University of California, Riverside, CA 92521, USA.

It is widely held that caloric restriction (CR) extends lifespan by preventing or reducing the age-related accumulation of irreversible molecular damage. In contrast, our results suggest that CR can act rapidly to begin life and health span extension, and that its rapid genomic effects are closely linked to its health effects. We found that CR begins to extend lifespan and reduce cancer as a cause of death within 8 weeks in older mice, apparently by reducing the rate of tumor growth. Further, 8 weeks of CR progressively reproduces nearly three quarters of the genomic effects of long-term CR (LTCR) in liver. Fewer of the genomic effects of LTCR are rapidly reproduced by the initiation of CR in the heart, but the changes produced are keys to cardiovascular health. Thus, the genomic effects of CR may be established more rapidly in mitotic than in postmitotic tissues. Most of the genomic effects of LTCR dissipate 8 weeks after switching to a control diet. Consistent with these results, others have shown that acute CR rapidly and reversibly reduces the short-term risk of death in Drosophila to that of LTCR treated flies. Further, in late adulthood, acute CR partially or completely reverses age-related alterations of liver, brain and heart proteins. CR also rapidly and reversibly mitigates biomarkers of aging in adult rhesus macaques and humans. These data argue that highly conserved mechanisms for the rapid and reversible enhancement of life- and health-span exist for mitotic and postmitotic tissues.

   
   
Med Hypotheses. 2005;64(1):201-8.
Aging: gene silencing or gene activation?
Burzynski SR.
Burzynski Clinic, 9432 Old Katy Road, Houston, TX 77055, USA.

According to the author's theory of gene silencing, the key process in aging involves reduced expression of a number of genes. Silencing of genes has a complex mechanism, which involves methylation of DNA, histone modification and chromatin remodeling. In addition to deacetylation of the histones and methylation of DNA, recently described RNAi mechanism could initiate formation of silenced chromatin. Hypermethylation of the promoter will silence the gene. Genome-wide hypomethylation will induce genomic instability, amplification of oncogenes and also silencing of the genes through RNAi mechanism. Studies by different groups, conducted in yeast, worms, flies and mice, confirmed substantial changes in gene expression in aging. Among them, the most important was silencing of tumor suppressors and other genes involved in the control of cell cycle, apoptosis, detoxification, and cholesterol metabolism. There was also increased expression of the smaller group of oncogenes and other genes which are associated with typical diseases of old age. Caloric restriction normalizes expression of a substantial percentage of these genes. Animal studies confirmed importance of caloric restriction, which decreases signaling through the IGF-1/AKT pathway and expression of gene p53. These studies, however, cannot be directly applied to human aging. It is proposed that age management therapy should attempt to normalize gene expression in the older population to the level typical for young adults. This would require activation of silenced genes and normalization of overexpressed genes. Caloric restriction and exercise are helpful in decreasing the activity of important oncogenes and activation of silenced tumor suppressors, and may have a positive impact, not only on aging, but also on prevention of cancer. Dietary supplements containing phytochemicals should normalize increased expression of oncogenes. Examples are: genistein and EGCG, which effect signaling through the IGF-1/AKT pathway and resveratrol and limonen, which do so through the RAS pathway. A group of amino acid derivatives and organic acids of animal and human origin should activate silenced tumor suppressor genes (Aminocare A10, Aminocare Extra). Among them 3-phenylacetylamino-2, 6-piperidinedione intercalates specifically with DNA and protects sequences of tumor suppressor genes, which are vulnerable to the effects of carcinogens. Phenylacetate activates p53 and p21 through inhibition of methyltransferase and farnesylation of the RAS protein. Phenylbutyrate activates tumor suppressor genes through inhibition of histone deacetylation. Phenylacetylglutamine decreases genomic instability and expression of oncogenes and promotes apoptosis. The application of DNA microarray techniques to human studies should provide more information about differences in gene expression in different age groups and help design more effective age management regimens.

   
   
Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5524-9.
Temporal linkage between the phenotypic and genomic responses to caloric restriction.
Dhahbi JM, Kim HJ, Mote PL, Beaver RJ, Spindler SR.
BioMarker Pharmaceuticals, Incorporated, 900 East Hamilton Avenue, Campbell, CA 95008, USA.

Caloric restriction (CR), the consumption of fewer calories while avoiding malnutrition, decelerates the rate of aging and the development of age-related diseases. CR has been viewed as less effective in older animals and as acting incrementally to slow or prevent age-related changes in gene expression. Here we demonstrate that CR initiated in 19-month-old mice begins within 2 months to increase the mean time to death by 42% and increase mean and maximum lifespans by 4.7 (P = 0.000017) and 6.0 months (P = 0.000056), respectively. The rate of age-associated mortality was decreased 3.1-fold. Between the first and second breakpoints in the CR survival curve (between 21 and 31 months of age), tumors as a cause of death decreased from 80% to 67% (P = 0.012). Genome-wide microarray analysis of hepatic RNA from old control mice switched to CR for 2, 4, and 8 weeks showed a rapid and progressive shift toward the gene expression profile produced by long-term CR. This shift took place in the time frame required to induce the health and longevity effects of CR. Shifting from long-term CR to a control diet, which returns animals to the control rate of aging, reversed 90% of the gene expression effects of long-term CR within 8 weeks. These results suggest a cause-and-effect relationship between the rate of aging and the CR-associated gene expression biomarkers. Therefore, therapeutics mimicking the gene-expression biomarkers of CR may reproduce its physiological effects.

   
   
Am J Physiol Endocrinol Metab. 2002 Jul;283(1):E38-43.
Effects of caloric restriction on mitochondrial function and gene transcripts in rat muscle.
Sreekumar R, Unnikrishnan J, Fu A, Nygren J, Short KR, Schimke J, Barazzoni R, Nair KS.
Endocrinology Division, Mayo Clinic, Rochester, Minnesota 55905, USA.

Rodent skeletal muscle mitochondrial DNA has been shown to be a potential site of oxidative damage during aging. Caloric restriction (CR) is reported to reduce oxidative stress and prolong life expectancy in rodents. Gene expression profiling and measurement of mitochondrial ATP production capacity were performed in skeletal muscle of male rats after feeding them either a control diet or calorie-restricted diet (60% of control diet) for 36 wk to determine the potential mechanism of the beneficial effects of CR. CR enhanced the transcripts of genes involved in reactive oxygen free radical scavenging function, tissue development, and energy metabolism while decreasing expression of those genes involved in signal transduction, stress response, and structural and contractile proteins. Real-time PCR measurements confirmed the changes in transcript levels of cytochrome-c oxidase III, superoxide dismutase (SOD)1, and SOD2 that were noted by the microarray approach. Mitochondrial ATP production and citrate synthase were unaltered by the dietary changes. We conclude that CR alters transcript levels of several genes in skeletal muscle and that mitochondrial function in skeletal muscle remains unaltered by the dietary intervention. Alterations in transcripts of many genes involved in reactive oxygen scavenging function may contribute to the increase in longevity reported with CR.

   
   
J Nutr Health Aging 1999;3(2):102-10
Caloric restriction and genomic stability.
Raffoul JJ, Guo Z, Soofi A, Heydari AR .
Department of Nutrition & Food Science, Wayne State University, Detroit, Michigan 48202, USA.

Caloric restriction (CR) without malnutrition is the only experimental manipulation that has consistently been shown to increase the mean and maximum lifespan of laboratory rodents. It has been suggested that CR extends the longevity of rodents and reduces the incidence of age-related pathological lesions by reducing the levels of DNA damage and mutations that accumulate with age within a cells genome. This hypothesis is attractive because the integrity of the genome is essential to a cell/organism and because it is supported by the observations that both cancer and immunological defects, which increase significantly with age and are delayed by CR, are associated with changes in DNA damage. However, all the evidence supporting the premise that the accumulation of DNA damage/mutations plays a role in aging and CR is correlative, i.e., the anti-aging action of CR-fed rodents is correlated with decreased DNA damage and mutation and increased DNA repair capacity. Therefore, additional experiments are required which employ more accurate assays of the DNA repair pathways as well as genetically engineered animal models to establish the role of specific DNA repair pathways and/or enzymes in the anti-aging action of CR. In this paper, we review the proposed mechanisms of DNA damage/repair while providing insight into current research that may assist in "unlocking" the mechanisms behind the life-prolonging effect of CR.

   
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FASTING / LOW CALORIE PROGRAMS
on the Adriatic Coast
The Anti-Aging Fasting Program consists of a 7-28 days program (including 3 - 14 fasting days). 7-28-day low-calorie diet program is also available .
More information
    The anti-aging story (summary)
Introduction. Statistical review. Your personal aging curve
  Aging and Anti-aging. Why do we age?
    2.1  Aging forces (forces that cause aging
     
Internal (free radicals, glycosylation, chelation etc.) 
External (Unhealthy diet, lifestyle, wrong habits, environmental pollution, stress, poverty-change "poverty zones", or take it easy. etc.) 
    2.2 Anti-aging forces
     
Internal (apoptosis, boosting your immune system, DNA repair, longevity genes) 
External (wellness, changing your environment; achieving comfortable social atmosphere in your life, regular intake of anti-aging drugs, use of replacement organs, high-tech medicine, exercise)
    2.3 Aging versus anti-aging: how to tip the balance in your favour!
 
    3.1 Caloric restriction and fasting extend lifespan and decrease all-cause mortality (Evidence)
      Human studies
Monkey studies
Mouse and rat studies
Other animal studies
    3.2 Fasting and caloric restriction prevent and cure diseases (Evidence)
        Obesity
Diabetes
Hypertension and Stroke
Skin disorders
Mental disorders
Neurogical disorders
Asthmatic bronchitis, Bronchial asthma
Bones (osteoporosis) and fasting
Arteriosclerosis and Heart Disease
Cancer and caloric restriction
Cancer and fasting - a matter of controversy
Eye diseases
Chronic fatigue syndrome
Sleeping disorders
Allergies
Rheumatoid arthritis
Gastrointestinal diseases
Infertility
Presbyacusis
    3.3 Fasting and caloric restriction produce various
      biological effects. Effects on:
        Energy metabolism
Lipids metabolism
Protein metabolism and protein quality
Neuroendocrine and hormonal system
Immune system
Physiological functions
Reproductive function
Radio-sensitivity
Apoptosis
Cognitive and behavioral functions
Biomarkers of aging
    3.4 Mechanisms: how does calorie restriction retard aging and boost health?
        Diminishing of aging forces
  Lowering of the rate of gene damage
  Reduction of free-radical production
  Reduction of metabolic rate (i.e. rate of aging)
  Lowering of body temperature
  Lowering of protein glycation
Increase of anti-aging forces
  Enhancement of gene reparation
  Enhancement of free radical neutralisation
  Enhancement of protein turnover (protein regeneration)
  Enhancement of immune response
  Activation of mono-oxygenase systems
  Enhance elimination of damaged cells
  Optimisation of neuroendocrine functions
    3.5 Practical implementation: your anti-aging dieting
        Fasting period.
Re-feeding period.
Safety of fasting and low-calorie dieting. Precautions.
      3.6 What can help you make the transition to the low-calorie life style?
        Social, psychological and religious support - crucial factors for a successful transition.
Drugs to ease the transition to caloric restriction and to overcome food cravings (use of adaptogenic herbs)
Food composition
Finding the right physician
    3.7Fasting centers and fasting programs.
  Food to eat. Dishes and menus.
    What to eat on non-fasting days. Dishes and menus. Healthy nutrition. Relation between foodstuffs and diseases. Functional foods. Glycemic index. Diet plan: practical summary. "Dr. Atkins", "Hollywood" and other fad diets versus medical science
     

Vegetables
Fruits
Bread, cereals, pasta, fiber
Glycemic index
Fish
Meat and poultry
Sugar and sweet
Legumes
Fats and oils
Dairy and eggs
Mushrooms
Nuts and seeds
Alcohol
Coffee
Water
Food composition

  Anti-aging drugs and supplements
    5.1 Drugs that are highly recommended
      (for inclusion in your supplementation anti-aging program)
        Vitamin E
Vitamin C
Co-enzyme Q10
Lipoic acid
Folic acid
Selenium
Flavonoids, carotenes
DHEA
Vitamin B
Carnitin
SAM
Vinpocetine (Cavinton)
Deprenyl (Eldepryl)
    5.2 Drugs with controversial or unproven anti-aging effect, or awaiting other evaluation (side-effects)
        Phyto-medicines, Herbs
HGH
Gerovital
Melatonin
      5.3 Drugs for treatment and prevention of specific diseases of aging. High-tech modern pharmacology.
        Alzheimer's disease and Dementia
Arthritis
Cancer
Depression
Diabetes
Hyperlipidemia
Hypertension
Immune decline
Infections, bacterial
Infections, fungal
Memory loss
Menopause
Muscle weakness
Osteoporosis
Parkinson's disease
Prostate hyperplasia
Sexual disorders
Stroke risk
Weight gaining
    5.4 The place of anti-aging drugs in the whole
      program - a realistic evaluation
 
    6.1 Early diagnosis of disease - key factor to successful treatment.
      Alzheimer's disease and Dementia
Arthritis
Cancer
Depression
Diabetes
Cataracts and Glaucoma
Genetic disorders
Heart attacks
Hyperlipidemia
Hypertension
Immune decline
Infectious diseases
Memory loss
Muscle weakness
Osteoporosis
Parkinson's disease
Prostate hyperplasia
Stroke risk
Weight gaining
    6.2 Biomarkers of aging and specific diseases
    6.3 Stem cell therapy and therapeutic cloning
    6.4 Gene manipulation
    6.5 Prosthetic body-parts, artificial organs
        Blood
Bones, limbs, joints etc.
Brain
Heart & heart devices
Kidney
Liver
Lung
Pancreas
Spleen
    6.6 Obesity reduction by ultrasonic treatment
  Physical activity and aging. Experimental and clinical data.
        Aerobic exercises
Stretching
Weight-lifting - body-building
Professional sport: negative aspects
 
  Conclusion: the whole anti-aging program
    9.1 Modifying your personal aging curve
      Average life span increment. Expert evaluation.
     
Periodic fasting and caloric restriction can add 40 - 50 years to your lifespan
Regular intake of anti-aging drugs can add 20-30 years to your lifespan
Good nutrition (well balanced, healthy food, individually tailord diet) can add 15-25 years to your lifespan
High-tech bio-medicine service can add 15-25 years to your lifespan
Quality of life (prosperity, relaxation, regular vocations) can add 15-25 years to your lifespan
Regular exercise and moderate physical activity can add 10-20 years to your lifespan
These approaches taken together can add 60-80 years to your lifespan, if you start young (say at age 20). But even if you only start later (say at 45-50), you can still gain 30-40 years


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    9.2 The whole anti-aging life style - brief summary 
    References eXTReMe Tracker
        The whole anti-aging program: overview
         
       

       
     
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