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Dr DIMITRIOS – JAMES MANOS

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REVIEW: CALORIE RESTRICTION (CR) THEORY & SUBSTANCES THAT MAY INCREASE LONGEVITY

Dr DIMITRIOS – JAMES MANOS
1 June 2011

I. CALORIE RESTRICTION (CR) THEORY

Calorie restriction (CR) theory supports a dietary regimen of restricted calorie intake, but not related to malnutrition, is supposed to improve age related health and longevity, by slowing aging process. In calorie restriction energy intake is decreased, however the intake of vitamins, minerals, elements and other important nutrients is sufficient. It has to -be reminded that western diet is hyper – caloric. This theory is supported to research on many animals (such as fish, dogs and rodents) and some fungi (such as yeast). Research on primitives, amongst them on human, is promising. Research started on 1934 when Mary Crowell and Clive McCay of Cornell University noticed that calorie restricted rats had increased lifespan up to twice. Since then, similar finding have ascertained to several animals and on fungi (1).

Calorie restriction (CR) is the only experimental manipulation that is known to extend the lifespan of a number of organisms including yeast, worms, flies, rodents and perhaps non-human primates. In addition, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer and cardiovascular disorders) in mammals. The mechanisms through which this occurs have been unclear. CR induces metabolic changes, improves insulin sensitivity and alters neuroendocrine function in animals. CR results in longevity and robust health, which might open new avenues of therapy for diseases of ageing (7).

A randomized controlled trial examined the effects of 6 months of calorie restriction, with or without exercise, in overweight, non-obese (body mass index, 25 to less than 30) men and women. Participants were randomized to 1 of 4 groups for 6 months: control (weight maintenance diet); calorie restriction (25% calorie restriction of baseline energy requirements); calorie restriction with exercise (12.5% calorie restriction plus 12.5% increase in energy expenditure by structured exercise); very low-calorie diet (890 kcal/d until 15% weight reduction, followed by a weight maintenance diet). The results showed that mean (SEM) weight change at 6 months in the 4 groups was as follows: controls, -1.0% (1.1%); calorie restriction, -10.4% (0.9%); calorie restriction with exercise, -10.0% (0.8%); and very low-calorie diet, -13.9% (0.7%). At 6 months, fasting insulin levels were significantly reduced from baseline in the intervention groups, but DHEAS and glucose levels were unchanged. Core body temperature was reduced in the calorie restriction and calorie restriction with exercise groups. After adjustment for changes in body composition, sedentary 24-hour energy expenditure was unchanged in controls, but decreased in the calorie restriction (-135 kcal/d [42 kcal/day]), calorie restriction with exercise (-117 kcal/d [52 kcal/day]), and very low-calorie diet (-125 kcal/day [35 kcal/day]) groups. These ‘metabolic adaptations’ (about 6% more than expected based on loss of metabolic mass) were statistically different from controls. DNA damage was also reduced from baseline in all intervention groups. The study concluded that 2 biomarkers of longevity (fasting insulin level and body temperature) are decreased by prolonged calorie restriction in humans and support the theory that metabolic rate is reduced beyond the level expected from reduced metabolic body mass (4).

Human studies have shown that calorie restriction reduces atherosclerosis risk factors. CR lowers cholesterol (and especially LDL cholesterol (‘bad’ cholesterol) and total cholesterol), triglycerides, fasting insulin, fasting glucose levels, CRP levels (an acute phase protein, it is increased e.g. in heart problems), and also lower BP (blood pressure), PDGF (Platelet Derivative Growth Factor) AB and lower BMI (Body Mass Index) and body fat percentage (1).

A study evaluated the effect of CR on risk factors for atherosclerosis (hardening of the arteries) in individuals who are restricting food intake to slow aging. In the study participated 18 individuals who had been on CR for an average of 6 years and 18 age-matched healthy individuals on typical American diets. They 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 results showed that the CR group were leaner than the comparison group (BMI body mass index, 19.6 ± 1.9 vs. 25.9 ± 3.2 kg/m²; percent body fat, 8.7 ± 7% vs. 24 ± 8%). Serum total cholesterol (Tchol), low-density lipoprotein (LDL) cholesterol (‘bad’ cholesterol), ratio of Tchol to high-density lipoprotein (HDL) cholesterol (HDL-C; ‘good’ cholesterol), triglycerides, fasting glucose, fasting insulin, C-reactive protein (CRP), platelet-derived growth factor AB (PDFG-AB), and systolic and diastolic blood pressure (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 intima-media thickness IMT was about 40% less in the CR group than in the comparison group. The study concluded that long-term CR has a powerful protective effect against atherosclerosis. This interpretation is supported by the finding of a low carotid artery intima-media thickness (IMT) (12).

Calorie restriction (CR) prolongs life in animals, but may reduce plasma HDL (high-density lipoprotein cholesterol; ‘good’ cholesterol), important in reverse cholesterol transport (RCT). The effect of CR, 60% of an ad libitum (AL) diet, on cholesterol removal from rectus femoris muscle injected with cationized LDL, was studied in C57BL male mice. RCT in vivo, on CR and AL diet, and cholesterol efflux from macrophages exposed to CR or AL sera, was similar, despite a 22% reduction in plasma HDL-cholesterol (HDL-C). In CR fed mice total cholesterol (TC) and phospholipid (T-PL) decreased by 32% and 38%, while HDL-C and HDL-PL decreased by 22% and 16% only, resulting in increased HDL-PL/T-PL ratio, which enhanced RCT. Partial re-feeding (CR-RF, 70% of AL) induced normalization of plasma lipids (excluding triglycerides), while HDL-PL/T-PL remained elevated. The study concluded that CR (calorie restriction) did not interfere with reverse cholesterol transport (RCT) in vivo, so it could possibly be beneficial to patients at risk for coronary heart disease (11).

Calorie restriction (CR) extends lifespan and reduces the incidence and age of onset of age-related disease in several animal models. The National Institute on Aging (NIA), in order to determine if this nutritional intervention has similar actions in a long-lived primate species, initiated a study in 1987 to investigate the effects of a 30% CR in male and female rhesus macaques (Macaca mulatta) monkeys of a broad age range. The results showed physiological effects of CR that were parallel with rodent studies and may be predictive of an increased lifespan. Specifically, results from the NIA study demonstrated that CR decreases body weight and fat mass, improves glucoregulatory (blood glucose regulation) function, decreases blood pressure and blood lipids, and decreases body temperature. Juvenile males exhibited delayed skeletal and sexual maturation. Adult bone mass was not affected by CR in females, nor were several reproductive hormones or menstrual cycling. Calorie restriction (CR) attenuated the age-associated decline in both dehydroepiandrosterone (DHEA) and melatonin in males. Although 81% of the monkeys in the study are still alive, preliminary evidence suggests that CR will have beneficial effects on morbidity and mortality (5).

A prospective 16 years follow-up study investigated the independent associations and the possible interaction of body mass index (BMI), leisure time physical activity (LTPA) and perceived physical fitness and functional capability with the risk of mortality. A regionally representative cohort of 35 – 63 years old Finnish men (n= 1 090 subjects) and women (n= 1122 subjects) participated. After adjustment for age, marital and employment status, perceived health status, smoking and alcohol consumption, the Cox proportional hazards model showed that BMI was not associated with the risk of death among the men or the women. Compared with the most active subjects the men and women with no weekly vigorous activity had relative risks of 1.61 and 4.68, respectively, for CVD (cardiovascular disease) mortality, and for the men there was a relative risk of 1.66 for CHD (coronary heart disease) mortality. When compared with the men who perceived their fitness as better than their age-mates, the men with the ‘worse’ assessment had a relative risk of 3.29 for all-cause mortality and 4.37 for CVD mortality. Men with at least some difficulty in walking a distance of 2 km had a relative risk of 1.62 for all-cause mortality, compared with those who had no functional difficulties. Also comparing with subjects with no functional difficulties, the men and women who had some difficulty climbing several flights of stairs had relative risks of 1.47 and 2.39 for all-cause mortality, respectively. For CVD mortality the relative risks were 1.85 and 3.38, respectively. The study concluded that although BMI did not prove to be an independent risk factor for mortality from CVD (cardiovascular disease), CHD (coronary heart disease) or from all causes combined; perceived physical fitness and functional capability did. An increase in LTPA (leisure time physical activity) seems to have a similar beneficial effect on the mortality risk of obese and non-obese men and women, and the effect also seems to be similar for fit and unfit subjects (10).

Recent studies suggest that calorie restriction (CR) may benefit Alzheimer’s disease (AD) by preventing amyloid-beta (Abeta) neuropathology in the mouse models of AD. Moreover, promotion of the NAD+-dependent SIRT1 mediated deacetylase activity, a key regulator in CR extension of life span, may be a mechanism by which CR influences AD-type neuropathology. A study explored the role of CR in AD-type brain amyloidosis in Squirrel monkeys (Saimiri sciureus). In the study, the monkeys were maintained on the normal and CR diets throughout their entire lifespan, until they died of natural causes. The study results showed that 30% of Squirrel monkeys that had CR diets had reduced contents of Abeta1-40 and Abeta1-42 peptides in the temporal cortex, relative to control (CON) fed monkeys. The decreased contents of cortical Abeta peptide inversely correlated with SIRT1 protein concentrations in the same brain region. However, no detectable change in total full-length amyloid-beta protein precursor (AbetaPP) level was found. Also 30% CR resulted in a select elevation of alpha- but not beta- or gamma- secretase activity which coincided with decreased ROCK1 protein content in the same brain region, relative to CON group. The study concluded that investigation of the role of calorie restriction (CR) in non-human primates may provide a valuable approach for further clarifying the role of CR in Alzheimer’s disease (AD) (9).

Calorie restriction increases longevity in many organisms, however it is unclear if calorie restriction/dieting contributes to cognitive impairment (6). Controversy exists as to whether lifelong 40% calorie restriction (CR) enhances, has no effect on, or disrupts cognitive function during aging. A study assessed the effects of CR versus ad-lib feeding on cognitive function in male Brown Norway x Fisher344 rats across a range of ages (8 – 38 months), using two tasks that are differentially sensitive to age-related cognitive decline: object recognition and Morris water maze (MWM). The results showed that all ages performed equally in object recognition, whereas, as a group, CR rats were impaired. Contrary, there was an age-related impairment in the MWM that was attenuated by CR as measured by time in proximity with and latency to reach the platform. Distance to the platform, a more sensitive measure, was not affected by CR. Also, calorie restriction (CR) resulted in an overall increase in physical activity, one of several behavioral confounders to consider in the interpretation of cognitive outcomes in both tasks (8).

A randomized controlled trial assessed the effect of 6 months of calorie restriction on cognitive functioning. In the study 48 participants were randomized to one of four groups: (1) control (weight maintenance), (2) calorie restriction (CR; 25% restriction), (3) CR plus structured exercise (CR + EX, 12.5% restriction plus 12.5% increased energy expenditure via exercise), or (4) low-calorie diet (LCD; 890 kcal/d diet until 15% weight loss, followed by weight maintenance). The results showed that no consistent pattern of verbal memory, visual retention/memory, or attention/concentration deficits were emerged during the trial. Daily energy deficit was not significantly associated with change in cognitive test performance. The study concluded that calorie restriction/dieting was not associated with a consistent pattern of cognitive impairment. Previous reports of cognitive impairment might reflect sampling biases or information processing biases (6).

Studies demonstrated in baker’s yeast cells a longevity gene that called Sir2 (silent information regulator 2), a sirtuine. This gene expanded lifespan by suppressing DNA instability. In mammals a similar gene is known as SIRT1. Many researchers support that the Sir2 gene is expressed on CR and this fact ends up to an increased longevity lifespan. Similar, in mammals, a CR diet ends up to an increased activity of the SIRT1 gene. It is suggested that a low-calorie diet that requires less nicotinamide adenine dinucleotide to metabolize may allow SIRT1 to be more active in its life-extending processes. Attempts are being made to develop CR mimetics. Resveratrol has been reported to activate Sir2/SIRT1 and extend the lifespan of yeast, nematode worms, fruit flies and mice consuming a high caloric diet, however it does not seem to extend lifespan in normal mice (1).

Calorie restriction (CR) extends lifespan in a wide spectrum of organisms and is the only regimen known to lengthen the lifespan of mammals. In a study they established a model of CR in budding yeast Saccharomyces cerevisiae. In this system, lifespan can be extended by limiting glucose or by reducing the activity of the glucose-sensing cyclic-AMP-dependent kinase (PKA). Lifespan extension in a mutant with reduced PKA activity requires Sir2 and NAD (nicotinamide adenine dinucleotide). In the study they explored how CR activates Sir2 to extend lifespan and showed that the shunting of carbon metabolism toward the mitochondrial tricarboxylic acid cycle and the concomitant increase in respiration play a central part in this process (2).

It has been suggested that calorie restriction may work by reducing the levels of reactive oxygen species (ROS) produced during respiration. In a study they mimicked calorie restriction in yeast by physiological or genetic means and showed a substantial extension in life-span. This extension was not observed in strains mutant for SIR2 (which encodes the silencing protein Sir2p) or NPT1 (a gene in a pathway in the synthesis of NAD, the oxidized form of nicotinamide adenine dinucleotide). The study concluded that the increased longevity induced by calorie restriction requires the activation of Sir2p by NAD (3).

In the budding yeast Saccharomyces cerevisiae, lifespan extension by calorie restriction (see above) requires the NAD1-dependent histone deacetylase, Sir2. It has been recently showed that Sir2 and its closest human homologue SIRT1, a p53 deacetylase, are strongly inhibited by the vitamin B3 precursor nicotinamide2. A study showed that increased expression of PNC1 (pyrazinamidase/nicotinamidase 1), which encodes an enzyme that deaminates nicotinamide, is both necessary and sufficient for lifespan extension by calorie restriction and low-intensity stress. PNC1, in the study, is identified as a longevity gene that is responsive to all stimuli that extend lifespan. The study showed that nicotinamide depletion is sufficient to activate Sir2 and that this is the mechanism by which PNC1 regulates longevity. The study concluded that yeast lifespan extension by calorie restriction is the consequence of an active cellular response to a low-intensity stress and speculate that nicotinamide might regulate critical cellular processes in higher organisms (2).

REFERENCE:

1.http://en.wikipedia.org/wiki/Calorie_restriction

2.http://seroudelab.biology.queensu.ca/pdf/anderson.pdf

3.http://seroudelab.biology.queensu.ca/pdf/lin.pdf

4.http://www.ncbi.nlm.nih.gov/pubmed/16595757

5.http://www.ncbi.nlm.nih.gov/pubmed/12543259

6.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664681/

7.http://www.nature.com/nrm/journal/v6/n4/abs/nrm1616.html

8.http://www.ncbi.nlm.nih.gov/pubmed/19420296

9.http://www.ncbi.nlm.nih.gov/pubmed/17183154

10.http://ukpmc.ac.uk/abstract/MED/11126344/reload=0;jsessionid=E12A26D3DF6685C1080A93E2E3520840.jvm1

11.http://www.ncbi.nlm.nih.gov/pubmed/12890475

12.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC404101/

II. SUBSTANCES THAT MAY INCREASE LONGEVITY

Resveratrol, a compound commonly found in red wine, has attracted many attentions recently. It is a diphenolic natural product accumulated in grapes and a few other species under stress conditions. It possesses a special ability to increase the life span of eukaryotic organisms, ranging from yeast, to fruit fly, to obese mouse (8).

Other substances that may increase longevity are: astragalus (however it is still under investigation), grapefruit, cranberry juice (it has the larger amounts of the antioxidants polyphenols), melatonin (however it is not recommended for prolonged use – more than 3 months), holy basil (Ocimum tenuiflorum, or tulsi) (not proved) and saffron (especially krokos kozanis, organic red saffron), garlic (especially aged garlic extract, also known as Kyolic), black tea, blueberries, royal jelly, cinnamon bark, Panax ginseng, Rhodiola and coenzyme Q10.

Polyphenols are the most abundant antioxidants found in food. They are known to have a protective effect against cardiovascular diseases and cancers and there is some evidence of neuroprotective effects. Sinclair et al examined a set of plant polyphenols for their effect on Sirt1 catalytic rate. These sirtuin-activating compounds (STACs) included butein, piceatannol, fisetin, quercetin and resveratrol (21).

Reprogramming of somatic cells to a pluripotent state was first accomplished using retroviral vectors for transient expression of pluripotency-associated transcription factors. The inhibition of the mammalian target of rapamycin (mTOR) pathway by rapamycin or PP242 enhances the efficiency of reprogramming to induced pluripotent stem cells (iPSCs). Inhibition of the insulin/IGF-1 signaling pathway, which like mTOR is involved in control of longevity, also enhances reprogramming efficiency. In addition, the small molecules used to inhibit these pathways also significantly improved longevity in Drosophila melanogaster. A study further tested the potential effects of six other longevity-promoting compounds on iPSC induction, including two sirtuin activators (resveratrol and fisetin), an autophagy inducer (spermidine), a PI3K (phosphoinositide 3-kinase) inhibitor (LY294002), an antioxidant (curcumin), and an activating adenosine monophosphate-activated protein kinase activator (metformin). With the exception of metformin, all of these chemicals promoted somatic cell reprogramming, though to different extents. The results show that the controllers of somatic cell reprogramming and organismal lifespan share some common regulatory pathways, which suggests a new approach for studying aging and longevity based on the regulation of cellular reprogramming (22).

In Drosophila melanogaster (fruit fly), in the wild-type strain Canton-S, lifespan was extended up to 23% with fisetin and up to 29% with resveratrol. A calorie-restricted diet increased fly lifespan by 40% in females and by 14% in males and, under these conditions, neither fisetin nor resveratrol further increased longevity, indicating that caloric restriction and resveratrol administration regulate a common genetic program controlling ageing. Resveratrol failed to extend lifespan in flies completely lacking functional Sir2 or in flies in which Sir2 is severely decreased. An independent investigation confirming the lifespan-promoting properties of resveratrol appeared, but a contradictory study disputes this notion (23).

Flavonoids present in many herbal edibles possess a remarkable spectrum of biochemical and pharmacological actions and they are assumed to exert beneficial effects to human health. Although the precise biological mechanisms of their action has not been elucidated yet, many of the protective properties of flavonoids are attributed to their antioxidative activity since oxidative stress is regarded as a main factor in the pathophysiology of various diseases and ageing. Oxidative stress results from excessive generation of reactive oxygen species (ROS) or diminished antioxidative defence and thus antioxidants are able to counteract such situations. A study used the multicellular model organism nematode Caenorhabditis elegans that is conserved in molecular and cellular pathways to mammals to examine the effects of the flavonoids kaempferol and fisetin with respect to their protective action in individual living worms. Both flavonoids increased the survival of C. elegans, reduced the intracellular ROS accumulation at lethal thermal stress, and diminished the extent of induced oxidative stress with kaempferol having a stronger impact. Kaempferol, but not fisetin, attenuated the accumulation of the ageing marker lipofuscin suggesting a life prolonging activity of this flavonoid. In addition to these effects that may be attributed to their antioxidative potential kaempferol and fisetin caused a translocation of the C. elegans FoxO transcription factor DAF-16 from the cytosol to the nucleus indicating a modulatory influence of both flavonoids on signalling cascade(s) (24).

For the relative research check the herbs/ dietary supplements at the above chapter III.POPULAR DIETARY SUPPLEMENTS & HERBS CATALOGUE (common names) WITH ALPHABETICAL ORDER

A study published in 6 October 2010 at the journal ‘‘Cell Metabolism’’ revealed that branched – chain amino acids (BCAAs) supplementation, and especially the amino acids leucine, isoleucine and valine, not only increases energy and stamina (power), but also it may lengthen lifespan and offer longevity. Branched-chain amino acids (BCAAs) have been shown to extend chronological life span in yeast. The study showed that a BCAA-enriched mixture (BCAAem) increased the average life span of mice. BCAAem supplementation increased mitochondrial biogenesis and sirtuin 1 expression in primary cardiac and skeletal myocytes and in cardiac and skeletal muscle, but not in adipose tissue and liver of middle-aged mice, and this was accompanied by enhanced physical endurance. Also, the reactive oxygen species (ROS) defense system genes were upregulated, and ROS production was reduced by BCAAem supplementation. All of the BCAAem-mediated effects were strongly attenuated in endothelial nitric oxide (NO) synthase null mutant mice. The study concluded to the important antiaging role of BCAAs mediated by mitochondrial biogenesis in mammals (1), (2), (3)

Another study showed that Cinnamon Bark and Ginseng in Herbal Formulas increase Life Span of Roundworms. Specifically, researchers at the University of Maryland, Baltimore, used the roundworm Caenorhabditis elegans (C. elegans) that has some genetic and biochemical similarities to humans to examine complex herbal preparations thought to combat adverse effects of aging. The above worms have a brief life span (about 20 days). In an NCCAM-funded study, researchers assessed two traditional Chinese multiherbal formulas—Huo Luo Xiao Ling Dan (HLXL), taken for chronic inflammatory pain (e.g., joint pain from arthritis); and Shi Quan Da Bu Tang (SQDB), taken to reduce fatigue and improve general wellness. They found that cinnamon bark, a component of both formulas, increased the worms’ life span. The researchers grew the worms in liquid containing HLXL, SQDB, or the individual herbal components of the formulas (HLXL has 11, SQDB has 10). The results showed that SQDB significantly extended the life span of the worm, but HLXL did not. The mean life span for the worms grown in SQDB was 22.3 days, an increase of 11.7 percent over the usual life span. Of all the individual components tested, only two significantly prolonged life span: Cinnamomum cassia bark (present in both formulas) and Panax ginseng root (present in SQDB only). The researchers concluded that Caenorhabditis elegans is a valid model for evaluating complex herbal preparations and may provide insight for future studies on longevity-promoting herbs (4).

PaMTH1 is an O-methyltransferase catalysing the methylation of vicinal hydroxyl groups of polyphenols. O-methylation is performed by O-methyltransferases which are members of the S-adenosylmethionine (SAM)-dependent O-methyltransferase superfamily involved in the secondary metabolism of many species across all kingdoms. The protein accumulates during ageing of Podospora anserina in both the cytosol and in the mitochondrial matrix. The construction and characterisation of a PaMth1 deletion strain provided additional evidence about the function of the protein in the protection against metal induced oxidative stress. Deletion of PaMth1 was found to lead to a decreased resistance against exogenous oxidative stress and to a shortened lifespan suggesting a role of PaMTH1 as a longevity assurance factor in a new molecular pathway involved in lifespan control (6). NOTE: This study does not make clear if SAMe helps in longevity.

In the budding yeast Saccharomyces cerevisiae, lifespan extension by calorie restriction (see above) requires the NAD1-dependent histone deacetylase, Sir2. It has been recently showed that Sir2 and its closest human homologue SIRT1, a p53 deacetylase, are strongly inhibited by the vitamin B3 precursor nicotinamide. A study showed that increased expression of PNC1 (pyrazinamidase/nicotinamidase 1), which encodes an enzyme that deaminates nicotinamide, is both necessary and sufficient for lifespan extension by calorie restriction and low-intensity stress. PNC1, in the study, is identified as a longevity gene that is responsive to all stimuli that extend lifespan. The study showed that nicotinamide depletion is sufficient to activate Sir2 and that this is the mechanism by which PNC1 regulates longevity. The study concluded that yeast lifespan extension by calorie restriction is the consequence of an active cellular response to a low-intensity stress and speculate that nicotinamide might regulate critical cellular processes in higher organisms (7).

Rhodiola is a plant root used in traditional Chinese medicine that may increase an organism's resistance to stress. It has been proposed that Rhodiola can extend longevity and improve health span by alleviating oxidative stress. In a study rhodiola supplied every other day at 30 mg/mL significantly increased the lifespan of Drosophila melanogaster (fruit fly). When comparing the distribution of deaths between Rhodiola-supplemented and control flies, Rhodiola-fed flies exhibited decelerated aging. Although the observed extension in lifespan was associated with statistically insignificant reductions in fecundity, correcting for a possible dietary restriction effect still did not eliminate the difference between supplemented and control flies, nor does the effect of Rhodiola depend on dietary manipulation, strongly suggesting that Rhodiola is not a mere dietary restriction mimetic. Although the study did not reveal the causal mechanism behind the effect of Rhodiola, it concluded that the supplement is worthy of continued investigation (9).

Panax ginseng is a well-known medicinal herb in North America and Europe. A study investigated the association between ginseng intake and mortality among members of the Korean population. The study examined 6 282 subjects who were 55 years of age or older. Adjusting for age, education, occupation, drinking, smoking, self-reported chronic disease, body mass index, and blood pressure, all-cause mortality for male ginseng users was significantly lower than that for male nonusers. However, such an association was not observed in women. Cancer-specific mortality was lower in female ginseng users than female nonusers after adjustment of relevant covariates. Compared to nonusers, the HR for cancer-specific mortality in women was 0.84 in infrequent users and 0.61 in frequent users, which is not statistically significant. The cancer-specific mortality was not associated with ginseng intake in male subjects. Mortality caused by cardiovascular diseases was not related to ginseng intake in both men and women. The 18.8-year progressive cohort study concluded that ginseng intake decreased all-cause mortality in older males, but such life prolongation effect was not shown in women (10).

Ageing results from complex genetically and epigenetically programmed processes that are elicited in part by noxious or stressful events that cause apoptosis (programmed cell death). A study reported that administration of spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells. Also, spermidine administration potently inhibited oxidative stress in ageing mice. In ageing yeast, spermidine treatment triggered epigenetic deacetylation of histone H3 through inhibition of histone acetyltransferases (HAT), suppressing oxidative stress and necrosis. Conversely, depletion of endogenous polyamines led to hyperacetylation, generation of reactive oxygen species, early necrotic death and decreased lifespan. The altered acetylation status of the chromatin led to significant upregulation of various autophagy-related transcripts, triggering autophagy in yeast, flies, worms and human cells. The study found that enhanced autophagy (the degradation of the cell’s components thru the lysosomal machinery) is crucial for polyamine-induced suppression of necrosis and enhanced longevity (12).

In another study it was found that reducing the concentration of polyamines (spermine, spermidine, and putrescine) in the body pool may slow the cancer process. Because dietary spermine, spermidine, and putrescine contribute to the body pool of polyamines, quantifying them in the diet is important. Of the foods from the database that were evaluated, fresh and frozen corn contain the highest levels of putrescine (560 000 nmol/serving and 902 880 nmol/serving) and spermidine (137 682 nmol/serving and 221 111 nmol/serving), and green pea soup contains the highest concentration of spermine (36 988 nmol/serving). The polyamine database and FFQ were tested with a convenience sample (n=165). Average daily polyamine intakes from the sample were: 159 133 nmol/day putrescine, 54 697 nmol/day spermidine, and 35 698 nmol/day spermine. Orange and grapefruit juices contributed the greatest amount of putrescine (44 441 nmol/day) to the diet. Green peas contributed the greatest amount of spermidine (3 283 nmol/day) and ground meat contributed the greatest amount of spermine (2 186 nmol/day) (11).

CBA, SHR, HER-2/neu and SAM mice revealed inhibition of age-related alterations in estrus function and spontaneous tumour development and showed life span extension under the influence of the pineal gland hormone Melatonin, synthetic peptide bioregulator Epitalon, delta-sleep-inducing peptide Deltaran, enterosorbent Aqualen and succinic acid containing preparation Neuronol (Noogam). The observed effect depended on the dose and conditions of administration, as well as genetic predisposition of the particular mice strains to tumour development (15).

From the age of 3 months until their natural deaths, female outbred Swiss-derived SHR mice were subcutaneously injected on 5 consecutive days every month with 0.1 ml of normal saline (control) or with 1.0 microg/mouse (approximately 30 – 40 microg/kg) of tetrapeptide Epitalon (Ala-Glu-Asp-Gly) dissolved in 0.1 ml saline. There were 54 mice in each group. The results of this study showed that treatment with Epitalon did not influence food consumption, body weight or mean life span of mice. However, it slowed down the age-related switching-off of estrous function and decreased the frequency of chromosome aberrations in bone marrow cells (by 17.1%). It also increased by 13.3% the life span of the last 10% of the survivors and by 12.3% the maximum life span in comparison with the control group. Also it was demonstrated that treatment with Epitalon did not influence total spontaneous tumor incidence, but inhibited the development of leukemia (6.0-fold), as compared with the control group. The data obtained suggest a geroprotector (that prevents the consequences of aging) activity of Epitalon and the safety of its long-term administration in mice (16).

Female SHR mice were fed the activated carbon fiber adsorbent Aqualen beginning at the age of 3 months through their life. The mice were fed Aqualen five times per week together with lab chow at a daily dose of 100 mg/kg b.w. The results showed that the addition of Aqualen into food did not significantly influence the dynamics of body weight and the mean life-span of the animals. At the same time, the age at 90% mortality of mice was 4 months longer in the group exposed to Aqualen. There were no statistically significant differences in the incidence of all tumors and malignant tumors in the group of mice treated with Aqualen, as compared with the control group. However, in the group of mice exposed to Aqualen, there was a 1.4 times reduction of the mean number of tumors per mouse. Feeding mice with the adsorbent led to a 4 months longer life-span in animals with any tumors and to a 5 months longer life-span in animals bearing malignant tumors. No carcinogenic effect of Aqualen was found. It could be supposed that Aqualen has some geroprotective (that prevents the consequences of aging) and anticarcinogenic properties (17).

In a study, treatment of female SAMP-1 mice with Neuronol (drug containing succinic acid) given with drinking water starting from the age of 2 months during the whole life prolonged the lifespan and markedly reduced mortality of animals aged 1.5 – 2 years. Neuronol inhibited the development of spontaneous tumors, primarily lymphomas, and significantly prolonged lifespan in mice with tumors. Long-term treatment with Neuronol had no pathological side effects. The experiments demonstrated geroprotective (that prevents the consequences of aging) and anticarcinogenic activity of Neuronol and safety of its long-term use (18).

Palmistry

Palmistry is concerned with the interpretation of the lines of the hand which indicate not only the development of various personality traits, but also indicated the constitution of physical well being and vitality while its length indicates natural life expectancy apart from accidents. A study showed the relationship between length of lifeline on the hand and age at death in 100 consecutive autopsies. A highly significant association between the two was discovered which was strengthened further when hand size was controlled for (5).

About sleep

Most of the people sleep 7 – 8 h per night. If someone is deprived of sleep, his/her performance suffers greatly; however, a few do well with just 3 – 4 h of sleep-a trait that seems to run in families. Determining which genes underlie this phenotype could shed light on the mechanisms and functions of sleep. A study performed mutagenesis in Drosophila melanogaster (fruit fly), because flies also sleep for many hours and, when sleep deprived, show sleep rebound and performance impairments. By screening 9 000 mutant lines, they found minisleep (mns), a line that sleeps for one-third of the wild-type amount. It was demonstrated that mns flies perform normally in a number of tasks, have preserved sleep homeostasis, but are not impaired by sleep deprivation. It was next demonstrated that mns flies carry a point mutation in a conserved domain of the Shaker gene. Furthermore, after crossing out genetic modifiers accumulated over many generations, other Shaker alleles also become short sleepers and fail to complement the mns phenotype. Finally, it was demonstrated that short-sleeping Shaker flies have a reduced lifespan. Shaker, which encodes a voltage-dependent potassium channel controlling membrane repolarization and transmitter release, may thus regulate sleep need or efficiency (19).

Based on data for 53 mammalian species reported in the literature, statistical analyses revealed that daily sleep quotas correlate positively with metabolic rate and negatively with maximum life span and brain weight. Sleep cycle length correlates positively with life span and brain weight and negatively with metabolic rate. Paradoxical sleep figures in these inter-correlations only by virtue of its positive correlation with slow wave sleep. The correlation between sleep time and metabolic rate suggests that sleep has the function of enforcing rest and limiting metabolic requirements, although some inconsistent findings are noted. Strong correlations of cycle length with brain weight and metabolic rate suggest that the significance of cycle length has not been sufficiently explored (14).

In a study, female SHR mice received 5-days long monthly courses of delta-sleep inducing peptide (DSIP) preparation ‘Deltaran’ subcutaneously in dose 5 mkg/kg during all their lives. It was demonstrated, that last 10% (most aged) of mice which received Deltaran lived for 16% longer than the controls. They had significantly higher amount of vertical activity in the ‘open field’ test, than the controls, starting from time when they were 6 months old and until their natural death. Mice of Deltaran group spent 73% more time in the open arms of elevated plus maze, and 9 times more often explored the extremities of this maze, than controls. Also Deltaran slowed the spontaneous carcinogenesis (cancer development) parameters. It is assumed that DSIP preparation ‘Deltaran’ have geroprotective (that prevents the consequences of aging), anxiolytic (control of anxiety) and antitumor activity (13).

The hypothesis that melatonin supplementation can increase the lifespan of a single-celled organism was tested by the administration of melatonin to the ciliated protozoan Paramecium tetraurelia. Melatonin supplementation in dim red light at a dose of 0.043 mM (10 mg/L) of nutrient media (bacterized Cerophyl) per day, followed by incubation for 23 hours in darkness, increased the mean clonal lifespan of Paramecium tetraurelia in days by percentages ranging from 20.8% to 24.2% over controls. Maximum clonal lifespan in days was also increased in melatonin-supplemented cells, from 14.8% to 24.0% over controls. Mean clonal lifespan in fissions was not significantly greater in melatonin-supplemented cells, with values ranging from 6.0% to 15.5% over controls. Maximum clonal lifespan in fissions did not differ appreciably, with values ranging from 1.0% to 9.1% over controls, except in the case of cells selected for rapid division rates, in which melatonin-supplemented cells (393 fissions) lived 20.9% longer than controls (325 fissions) in terms of cumulative cell doublings during the clonal lifespan. The finding that melatonin supplementation increased clonal lifespan in Paramecium tetraurelia, an aerobic, single-celled organism, suggests that the mechanism of melatonin’s longevity-promoting effects may be intracellular (20).