Anti-Aging Publications

Armstrong SM, Redman JR. Melatonin: a chronobiotic with ANTI-AGING properties? Med Hypotheses 1991, 34(4):300-9

Recently, it has been reported that melatonin administration extends the lifespan of mice, a finding which supports previous research on the effects of pinealectomy and pineal extract administration. The prolongation of lifespan by melatonin has been interpreted in favour of an upregulation of the immune system as well as due to anti-stress properties of melatonin acting via the brain opioid system. In this paper we offer an alternative explanation of melatonin's anti-aging effect: the circadian pacemaker system has a diminished amplitude with age as indexed by a decrease in circulating melatonin levels. Stability of the circadian system correlates with its amplitude and loss of circadian amplitude produces lability which, in turn, leads to internal temporal disorder. Internal temporal disorder may be a precursor of disease states. Exogenous melatonin increases the amplitude of the circadian pacemaker system by feedback onto that system. The hypothalamic suprachiasmatic nuclei are thought to be the mammalian biological clock in the brain and have high concentrations of melatonin receptors. Therefore, melatonin administration in pharmacological doses may prevent aging symptoms by acting at the level of the circadian pacemaker's amplitude.

No abstract available at this time

Boldyrev AA, Gallant SC, Sukhich GT. Carnosine, the protective, ANTI-AGING peptide. Biosci Rep 1999, 19(6):581-7

Carnosine attenuates the development of senile features when used as a supplement to a standard diet of senescence accelerated mice (SAM). Its effect is apparent on physical and behavioral parameters and on average life span. Carnosine has a similar effect on mice of the control strain, but this is less pronounced due to the non-accelerated character of their senescence processes.

Cavallini G, Donati A, Gori Z, Pollera M, Bergamini E. The protection of rat liver autophagic proteolysis from the age-related decline co-varies with the duration of ANTI-AGEING food restriction. Exp Gerontol 2001 36(3):497-506

Restricting caloric intake (CR) well below that of ad libitum (AL) fed animals retards and/or delays many characteristics of ageing and the occurrence and progression of age-associated diseases, efficacy depending on duration. The hypothesis that the anti-ageing effect of CR might involve stimulation of the cell-repair mechanism autophagy was tested. The effects of ageing and duration of anti-ageing CR on liver autophagic proteolysis (AP) were explored in male AL Sprague-Dawley rats aged 2-, 6-, 12- and 24-months; and 24-month-old rats on a CR diet initiated at 2-, 6- and 12-month of age or initiated at age 2-months and interrupted at age 18 months. The age-related changes in the regulation of AP were studied by monitoring the rate of valine release in the incubation medium from isolated liver cells by an HPLC procedure. Results show that the maximum attainable rate and the regulation of AP decline with increasing age; that changes are prevented by anti-ageing CR initiated at young age, that the protective effects of CR change with the duration of diet. It is concluded that the data are compatible with the hypothesis that AP and improved membrane maintenance might be involved in the antiageing mechanism of CR.

Chiba T, Yamaza H, Higami Y, Shimokawa I. ANTI-AGING effects of caloric restriction: Involvement of neuroendocrine adaptation by peripheral signaling. Microscopy Research and Technique, 2002 Nov 15;59(4):317-24.

Many hormonal signals from peripheral tissues contribute to the regulation of energy homeostasis and food intake. These regulators including leptin, insulin, and ghrelin, modulate the orexigenic and anorexigenic neuropeptide expression in hypothalamic nuclei. The anti-aging effects of caloric restriction have been explained from an evolutional viewpoint of the adaptive response of the neuroendocrine and metabolic response systems to maximize survival during periods of food shortage. In organisms, excess energy is stored in adipose tissues as a triglyceride preparation for such survival situations. Adipose tissue has recently been recognized as an endocrine organ, and leptin, as secreted by adipocyte, seems to be an especially important factor for the adaptive response to fasting and neuroendocrine alterations under caloric restriction. In this review, we discuss the potential involvement of neuroendocrine modulators in longevity and the anti-aging effects of caloric restriction.

Chung HY, Kim HJ, Kim KW, Choi JS, Yu BP. Molecular inflammation hypothesis of aging based on the ANTI-AGING mechanism of calorie restriction. Microscopy Research and Technique, 2002 Nov 15;59(4):264-72.

De Grey AD. Challenging but essential targets for genuine ANTI-AGEING drugs. Expert Opin Ther Targets 2003, 7(1): 1-5.

Donati A, Cavallini G, Paradiso C, Vittorini S, Pollera M, Gori Z, Bergamini E. Age-related changes in the autophagic proteolysis of rat isolated liver cells: Effects of ANTIAGING dietary restrictions. Journals of Gerontology Series A-Biological Sciences and Medical Sciences, 2001, 56 (9): B375-B383.

Autophagy is a process that sequesters and degrades organelles and macromolecular constituents of cytoplasm for cellular restructuring and repair and as a source of nutrients for metabolic use in early starvation. The effects of two antiaging dietary regimens (initiated in rats at the age of 2 months), namely, 40% dietary restriction (DR) and every-other-day ad-libitum feeding, that exhibited different effects on metabolism and similar effects on longevity on the age-related changes in the regulation of autophagic proteolysis were studied by monitoring the rate of valine release in the incubation medium from isolated liver cells of male albino Sprague-Dawley rats aged 2, 6, 12, 18, 24, and 27 months. (The liver cells were incubated in vitro with added amino acids and 10(-7) M insulin or glucagon.) Age-matched male albino Sprague-Dawley rats fed ad libitum served as a control. Results show that in ad-libitum-fed rats, after a transient increase by age 6 months, autophagic proteolysis and regulation by amino acid exhibit a dramatic age-related decline, and that the age-related changes are prevented by dietary antiaging intervention. A comparison shows that the protective effects of DR and every-other-day ad-libitum feeding are partially different in 24-month-old rats (but the beneficial effects of the two diets on regulation of autophagic proteolysis are always similar). With regard to endocrine regulation, results confirm that the liver cell response to glucagon (but not to insulin) declines with increasing age, and they show that antiaging DRs significantly improve the effects of glucagon (and have no effect on the response to insulin). The interactions of age by diet, glucagon (and in older rats, insulin), and amino acids are significant. It is concluded that DR significantly improves the susceptibility of liver cells to lysosomal degradation, and it prevents decline with increasing age. It is suggested that improved liver autophagy and lysosomal degradation might be part of the antiaging mechanisms of DR.

Everitt A, Meites J. Aging and ANTI-AGING effects of hormones. J Gerontol 1989, 44(6): B139-47.

Hormones can promote or inhibit aging depending on the experimental conditions employed. The aging effects of hormones are demonstrated by reducing hormone secretion by hypophysectomy or chronic underfeeding in young or mature rats. These result in depressing whole body metabolism, growth, body temperature and blood glucose levels, heart rate and vital capacity, gene expression, etc., but delaying aging of tissues, suppressing development of pathology and tumors, and, in underfed rats, prolonging life span. The anti-aging effects of hormones are demonstrated by elevating hormone levels in old rats whose hormones have declined as a result of dysfunctions that develop in the neuroendocrine system with age. An increase of hormones in these rats promotes gene expression, elevates protein synthesis, and enhances metabolism, growth, and function of stimulated organs and tissues.

Everitt AV, Wyndham JR, Barnard DL. The ANTI-AGING action of hypophysectomy in hypothalamic obese rats: effects on collagen aging, age-associated proteinuria development and renal histopathology. Mech Ageing Dev 1983, 22(3-4): 233-51

Hypophysectomy in young male Wistar rats aged 70 days, like food restriction begun at the same age, retarded the life-long rate of collagen aging in tail tendon fibres and inhibited the development of age-associated proteinuria and renal histopathology. Hypothalamic lesions which increased the food intake of hypophysectomized rats from 7 g to 15 g/day and produced obesity did not alter the rate of either collagen aging or proteinuria development, nor reduce life expectancy, but increased the incidence of abnormal glomeruli. In the intact rats elevation of food intake from 7 g to 15 g/day increased the rate of proteinuria development, but did not affect the rate of collagen aging. Hypophysectomy was found to have a greater anti-collagen aging effect than food restriction, when food intakes were the same in both groups. These studies suggest a pituitary-hormonal effect on collagen aging and a food-pituitary-hormone-mediated effect on the development of age-associated proteinuria.

Floyd RA, Hensley K, Forster MJ, Kelleher-Anderson JA, Wood PL. Nitrones as neuroprotectants and ANTIAGING drugs. Increasing Healthy Life Span: Conventional Measures And Slowing The Innate Aging Process. Annals of the New York Academy of Sciences 2002, 959: 321-329.

Specific nitrones have been used for more than 30 years in analytical chemistry and biochemistry to trap and stabilize free radicals for the purpose of their identification and characterization. PBN (alpha-phenyl-tert-butyl nitrone), one of the more widely used nitrones for this purpose, has been shown to have potent pharmacologic activities in models of a number of aging-related diseases, most notably the neurodegenerative diseases of stroke and Alzheimer's disease. Studies in cell and animal models strongly suggest that PBN has potent antiaging activity. A novel nitrone, CPI-1429, has been shown to extend the life span of mice when administration was started in older animals. It has also shown efficacy in the prevention of memory dysfunction associated with normal aging in a mouse model. Mechanistic studies have shown that the neuroprotective activity of nitrones is not due to mass-action free radical-trapping activity, but due to cessation of enhanced signal transduction processes associated with neuroinflammatory processes known to be enhanced in several neurodegenerative conditions. Enhanced neuroinflammatory processes produce higher levels of neurotoxins, which cause death or dysfunction of neurons. Therefore, quelling of these processes is considered to have a beneficial effect allowing proper neuronal functioning. The possible antiaging activity of nitrones may reside in their ability to quell enhanced production of reactive oxygen species associated with age-related conditions. On the basis of novel ideas about the action of secretory products formed by senescent cells on bystander cells, it is postulated that nitrones will mitigate these processes and that this may be the mechanism of their antiaging activity.

Ghanta VK, Hiramoto NS, Hiramoto RN. Thymic peptides as ANTI-AGING drugs: effect of thymic hormones on immunity and life span. Int J Neurosci 1990, 51(3-4):371-2.

Heydari AR and A. Richardson. Does gene expression play any role in the mechanism of the ANTIAGING effect of dietary restriction? Ann NY Acad Sci 1992, 663: 384-395.

Hipkiss AR. Carnosine, a protective, ANTI-AGEING peptide? Int J Biochem Cell Biol 1998, 30(8):863-8

Carnosine (beta-alanyl-L-histidine) has protective functions additional to anti-oxidant and free-radical scavenging roles. It extends cultured human fibroblast life-span, kills transformed cells, protects cells against aldehydes and an amyloid peptide fragment and inhibits, in vitro, protein glycation (formation of cross-links, carbonyl groups and AGEs) and DNA/protein cross-linking. Carnosine is an aldehyde scavenger, a likely lipofuscin (age pigment) precursor and possible modulator of diabetic complications, atherosclerosis and Alzheimer's disease.

Hipkiss AR, Brownson C. A possible new role for the ANTI-AGEING peptide carnosine. Cell Mol Life Sci 2000, 57(5):747-53

The naturally occurring dipeptide carnosine (beta-alanyl-L-histidine) is found in surprisingly large amounts in long-lived tissues and can delay ageing in cultured human fibroblasts. Carnosine has been regarded largely as an anti-oxidant and free radical scavenger. More recently, an anti-glycating potential has been discovered whereby carnosine can react with low-molecular-weight compounds that bear carbonyl groups (aldehydes and ketones). Carbonyl groups, arising mostly from the attack of reactive oxygen species and low-molecular-weight aldehydes and ketones, accumulate on proteins during ageing. Here we propose, with supporting evidence, that carnosine can react with protein carbonyl groups to produce protein-carbonyl-carnosine adducts ('carnosinylated' proteins). The various possible cellular fates of the carnosinylated proteins are discussed. These proposals may help explain anti-ageing actions of carnosine and its presence in non-mitotic cells of long-lived mammals.

Hipkiss AR, Brownson C. Carnosine reacts with protein carbonyl groups: another possible role for the ANTI-AGEING peptide? Biogerontology 2000, 1(3):217-23

Carnosine (beta-alanyl-L-histidine) can delay senescence and provoke cellular rejuvenation in cultured human fibroblasts. The mechanisms by which such a simple molecule induces these effects is not known despite carnosine's well documented anti-oxidant and oxygen free-radical scavenging activities. Carbonyl groups are generated on proteins post-synthetically by the action of reactive oxygen species and glycating agents and their accumulation is a major biochemical manifestation of ageing. We suggest that, in addition to the prophylactic actions of carnosine, it may also directly participate in the inactivation/disposal of aged proteins possibly by direct reaction with the carbonyl groups on proteins. The possible fates of these 'carnosinylated' proteins including the formation of inert lipofuscin, proteolysis via the proteasome system and exocytosis following interaction with receptors are also discussed. The proposal may point to a hitherto unrecognised mechanism by which cells/organisms normally defend themselves against protein carbonyls.

Hipkiss AR. On the ANTI-AGING activities of aminoguanidine and N-t-butylhydroxylamine. Mech Ageing Dev 2001, 122 (2): 169-171.

Hipkiss AR, Brownson C, Carrier MJ. Carnosine, the ANTI-AGEING, anti-oxidant dipeptide, may react with protein carbonyl groups. Mech Ageing Dev 2001, 122(13):1431-45

Carnosine (beta-alanyl-L-histidine) is a physiological dipeptide which can delay ageing and rejuvenate senescent cultured human fibroblasts. Carnosine's anti-oxidant, free radical- and metal ion-scavenging activities cannot adequately explain these effects. Previous studies showed that carnosine reacts with small carbonyl compounds (aldehydes and ketones) and protects macromolecules against their cross-linking actions. Ageing is associated with accumulation of carbonyl groups on proteins. We consider here whether carnosine reacts with protein carbonyl groups. Our evidence indicates that carnosine can react non-enzymically with protein carbonyl groups, a process termed 'carnosinylation'. We propose that similar reactions could occur in cultured fibroblasts and in vivo. A preliminary experiment suggesting that carnosine is effective in vivo is presented; it suppressed diabetes-associated increase in blood pressure in fructose-fed rats, an observation consistent with carnosine's anti-glycating actions. We speculate that: (i) carnosine's apparent anti-ageing actions result, partly, from its ability to react with carbonyl groups on glycated/oxidised proteins and other molecules; (ii) this reaction, termed 'carnosinylation,' inhibits cross-linking of glycoxidised proteins to normal macromolecules; and (iii) carnosinylation could affect the fate of glycoxidised polypeptides.

Kitani K, Minami C, Isobe K, Maehara K, Kanai S, Ivy GO, Carrillo MC. Why (-)deprenyl prolongs survivals of experimental animals: Increase of anti-oxidant enzymes in brain and other body tissues as well as mobilization of various humoral factors may lead to systemic ANTI-AGING effects. Mech Ageing Dev 2002, 123 (8): 1087-1100.

(-)Deprenyl, a monoamine oxidase B (MAO B) inhibitor is known to upregulate activities of anti-oxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) in brain dopaminergic regions. The drug is also the sole chemical which has been repeatedly shown to increase life spans of several animal species including rats, mice, hamsters and dogs. Further, the drug was recently found to enhance anti-oxidant enzyme activities not only in brain dopaminergic regions but also in extra-brain tissues such as the heart, kidneys, adrenal glands and the spleen. We and others have also observed mobilization of many humoral factors (interferone (INF)-gamma, tumor necrosis factor (TNF)-alpha, interleukine (IL)-1beta,2,6, trophic factors, etc.) and enhancement of natural killer (NK) cell functions by (-)deprenyl administration. An apparent extension of life spans of experimental animals reported in the past may be better explained by these new observations that ( -)deprenyl upregulate SOD and CAT activities not only in the brain but also in, extra-brain vital organs and involve anti-tumorigenic as well as immunomodulatory effect as well. These combined drug effects may lead to the protection of the homeostatic regulations of the neuro-immuno-endocrine axis of an organism against aging.

Knoll J. ANTIAGING compounds: (-)deprenyl (selegiline) and (-)1-(benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective highly potent enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain. CNS Drug Reviews 2001, 7 (3): 317-345

Hundreds of millions of people now die over the age of 80 years primarily due to twentieth century progress in hygiene, chemotherapy, and immunology. With a longer average lifespan, the need to improve quality of life during the latter decades is more compelling. "Aging - The Epidemic of the New Millenium," a recent international conference (Monte Carlo, June 17-18, 2000), showed with peculiar clarity that a safe and efficient drug strategy to slow the age-related decay of brain performance is still missing. This review summarizes the physiologic and pharmacologic arguments in favor of a peculiar lifelong prophylactic medication with reasonable chances to keep in check brain aging and decrease the precipitation of age-related neurological diseases.

Lane MA, Ingram DK, Roth GS. The serious search for an ANTI-AGING pill. Scientific American 2002, 287 (2): 36-41.

Lane MA, Baer DJ, Rumpler WV, Weindruch R, Ingram DK, Tilmont EM, Cutler RG, Roth GS Calorie restriction lowers body temperature in rhesus monkeys, consistent with a postulated ANTI-AGING mechanism in rodents. Proceedings of the National Academy of Sciences of the United States of America 1996, 93 (9): 4159-4164

Many studies of caloric restriction (CR) in rodents and lower animals indicate that this nutritional manipulation retards aging processes, as evidenced by increased longevity, reduced pathology, and maintenance of physiological function in a more youthful state. The anti-aging effects of CR are believed to relate, at least in part, to changes in energy metabolism. We are attempting to determine whether similar effects occur in response to CR in nonhuman primates. Core (rectal) body temperature decreased progressively with age from 2 to 30 years in rhesus monkeys fed ad lib (controls) and is reduced by approximate to 0.5 degrees C in age-matched monkeys subjected to 6 years of a 30% reduction in caloric intake. A short-term (1 month) 30% restriction of 2.5-year-old monkeys lowered subcutaneous body temperature by 1.0 degrees C. Indirect calorimetry showed that 24-hr energy expenditure was reduced by approximately 24% during short-term CR. The temporal association between reduced body temperature and energy expenditure suggests that reductions in body temperature relate to the induction of an energy conservation mechanism during CR. These reductions in body temperature and energy expenditure are consistent with findings in rodent studies in which aging rate was retarded by CR, now strengthening the possibility that CR may exert beneficial effects in primates analogous to those observed in rodents.

Masoro EJ. Potential role of the modulation of fuel use in the ANTIAGING action of dietary restriction. Ann N Y Acad Sci 1992, 663:403-11

Masoro EJ. ANTIAGING action of caloric restriction: endocrine and metabolic aspects. Obes Res 1995, 3 Suppl 2:241s-247s

Restricting the energy intake of mice and rats slows the rate of actuarial aging, delays or prevents most age-associated disease processes, and maintains physiological processes in a youthful state at advanced ages. This manipulation is effective when initiated in young animals or in adult life. Although body fat is decreased by this reduction in energy intake, the reduction in body fat is not causally related to the antiaging action. Nor does this reduction in energy intake slow the aging processes by decreasing the metabolic rate, but it may do so by altering the characteristics of fuel use. Another possible mechanism underlying the antiaging action is the general protection restriction of energy intake provides against harmful agents, an action which may be the result of an alteration in adrenal glucocorticoid physiology.

Masoro EJ. Possible mechanisms underlying the ANTIAGING actions of caloric restriction. Toxicol Pathol 1996, 24(6):738-41

Restricting the food intake of mice and rats to well below that of ad libitum-fed animals markedly slows the aging processes. This action is reflected in an increase in longevity, a decrease in the age-associated increase in age-specific mortality rate, the maintenance of the physiological processes in a youthful state even at advanced ages, and the delaying of the onset or slowing of the progression or both of most age-associated diseases. The dietary factor responsible is the reduction in energy (caloric) intake. Many hypotheses have been proposed regarding mechanisms underlying this antiaging action. Hypotheses relating the antiaging action to the retardation of growth and development, the reduction of adipose mass, and the reduction of metabolic rate have been found to be wanting. Two of the proposed hypotheses have some evidence in their support. One involves the altered metabolic characteristics of glucose fuel use and of oxidative metabolism. The other relates to the enhanced ability of the rodents restricted in food intake to cope with challenges, which in turn has been linked to the glucocorticoid system and to the heat-shock protein system.

Masoro EJ. Hormesis and the ANTIAGING action of dietary restriction. Exp Gerontol 1998, 33(1-2):61-6

Hormesis refers to the often encountered phenomenon of a beneficial biological action from a factor or agent that is generally viewed as detrimental. Beneficial actions that have been observed include life span extension. It is proposed that life span extension in rodents by dietary restriction is an example of hormesis and that sustained moderate hyperadrenocorticism underlies this life prolongation. Evidence supporting this concept is presented. The possibility is also suggested that whenever hormesis leads to an extension of mammalian life span, it is likely that moderate hyperadrenocorticism plays a major role.

Masoro EJ, Austad SN. The evolution of the ANTIAGING action of dietary restriction: a hypothesis. J Gerontol A Biol Sci Med Sci 1996, 51(6): B387-91

Reducing the intake of dietary energy by laboratory rodents to well below that of animals allowed to eat ad libitum slows the rate of aging. This phenomenon, which is robust and reproducible, is known as the antiaging action of dietary restriction (DR). We hypothesize that this DR response arose because of its evolutionary advantage with respect to survival during periods of unpredictable, short-term food shortage. In our evolutionary scenario, food shortage led to an adaptive redirection of resources away from reproduction toward somatic maintenance via an enhanced heat shock protein response in invertebrates. In vertebrates, an additional involvement of the hypothalamic-adenohypophyseal-adrenal glucocorticoid system was necessitated to protect against excessive systemic defense responses. We suggest several general implications of our hypothesis.

Meites J. ANTI-AGEING interventions and their neuroendocrine aspects in mammals. J. Reprod. Fertil., Suppl 1993, 46:1-9.

A number of interventions for delaying or reversing declines in body functions due to ageing are critically reviewed here, including their relation to neuroendocrine function. Diets severely deficient in calories retard the ageing of body tissues, inhibit the development of disease and tumours, and significantly prolong the lifespan of rats and mice. Such diets also decrease hormone secretion, reduce the metabolism of the whole body, and lower gene expression. Administration of hormones, thymic peptides and other immune factors, and appropriate drugs can improve declining immune function in old rats and mice, thereby increasing resistance to infection, autoimmune disease and tumours. In old rats, correction of faults that develop in the neuroendocrine system with age--particularly in the hypothalamus--can restore oestrous cycles, increase the secretion of growth hormone, increase protein synthesis, inhibit development of disease and tumours, and prolong life. Antioxidants administered to rats and mice in an attempt to reduce damage to cells caused by free radicals, do not significantly retard ageing or prolong the lifespan of these animals. Regular, moderate exercise in elderly humans decreases incidence of heart disease, improves lung function, reduces bone loss, and produces other beneficial effects. Suitable drugs that will improve memory function in elderly humans remain to be developed, although a few have produced small improvements albeit with undesirable side effects. Overall, the neuroendocrine and immune approaches offer the best prospects for delaying and reversing declines in body functions due to ageing.

Moriguchi T, Saito H, Nishiyama N. ANTI-AGEING effect of aged garlic extract in the inbred brain atrophy mouse model. Clin. Exp. Pharmacol. Physiol. 1997, 24(3-4):235-42

1. The effects of chronically administered aged garlic extract (AGE) on the age-related changes in a novel strain of senescence accelerated mouse (SAM) characterized by age-related brain atrophy (SAMP10) were investigated. 2. A solid diet containing 2% (w/w) AGE was given to SAM from 2 months of age. 3. The grading score of senescence in SAMP10 at 10 months of age was significantly higher than that of SAMR1, a reference strain for SAMP10. 4. Administration of AGE prevented the increase in the grading score of SAMP10 and SAMR1. 5. In behavioural evaluation, AGE improved learning and memory deficits of SAMP10 in both the passive and conditioned avoidance tests as well as the spatial memory test. 6. Treatment with AGE in SAMP10 prevented the decrease in brain weight and the atrophic changes in frontal brain at 12 months of age. 7. These results raise the possibility that AGE prevents physiological ageing and may be beneficial for age-related cognitive disorders in humans.

Nawata H, Yanase T, Goto K, Okabe T, Ashida K. Mechanism of action of ANTI-AGING DHEA-S and the replacement of DHEA-S. Mech Ageing Dev 2002, 123 (8): 1101-1106.

The plasma ACTH and cortisol levels do not change during aging. On the other hand, the plasma dehydroepiandrosterone sulfate (DHEA-S) changes remarkably during aging. Before puberty, the plasma DHEA-S level both in males and females is very low, however, it rapidly increases at puberty, and thereafter significantly decreases both linearly and age-dependently. Cytochrome P450c17 has two enzyme activities, 17-alpha-hydroxylase and 17,20-lyase. Cortisol is synthesized by 17-a-hydroxylase, and DHEA is synthesized by 17,20-lyase. The mechanism of dissociation of cortisol and DHEA synthesis in aging depends on another regulator of 17,20-lyase of cytochrome P450c17 such as cytochrome P450 reductase. We demonstrated significant decrease in cytochrome P450 reductase activity in bovine aged adrenal glands. We clarified the beneficial effects of DHEA as an anti-aging steroid based on both in vitro and in vivo experiments, such as the stimulatory effect of immune system, anti-diabetes mellitus, anti-atherosclerosis, anti-dementia (neurosteroid), anti-obesity and anti-osteoporosis. It is very important to identify the mechanism of action of DHEA. We clarified the conversion of DHEA to estrone by cytochrome P450 aromatase in primary cultured human osteoblasts. We indentified high affinity of DHEA binding with K-d = 6.6 nM in antigen and DHEA stimulated human T lymphocytes. We searched for the target genes that are specifically induced in activated T lymphocytes in the presence of DHEA by subtractive hybridization screening for differentially expressed transcripts. The double blind, randomized human replacement therapies utilizing DHEA are also reviewed.

Novelli M, Masiello P, Bombara M, Bergamini E. Protein glycation in the aging male Sprague-Dawley rat: effects of ANTIAGING diet restrictions. J Gerontol A Biol Sci Med Sci 1998, 53(2):B94-101

Protein glycation and accumulation of advanced glycosylated end-products (AGEs) are supposed to play an important role in the process of aging. Dietary restriction increases life span and delays the onset of most age-associated diseases. Age-dependent changes in glucose homeostasis and glycated plasma proteins and hemoglobin were determined, and AGEs formation was measured as fluorescence in skin and aortic collagens in male Sprague-Dawley rats fed ad libitum or subjected to every-other-day feeding or 40% food restriction. In aging control rats, skin and aortic collagen-linked fluorescence increased with a similar exponential curve (aortic value being always higher), whereas glycated plasma protein and hemoglobin decreased slightly. Dietary restrictions decreased glycated plasma proteins and fluorescent products in skin collagen of younger but not older rats, and did not affect glycated hemoglobin or aortic collagen fluorescence. In conclusion, our data indicate that age-related changes in glucose homeostasis do not play a substantial role in aging; and collagen-linked fluorescence increases significantly during aging, but it may not be sensitive to dietary intervention.

Oxenkrug G, Requintina P, Bachurin S. Antioxidant and ANTIAGING activity of N-acetylserotonin and melatonin in the in vivo models. Neuroprotective Agents. Annals of The New York Academy of Sciences 2001, 939: 190-199.

It is generally accepted that antioxidant properties of melatonin significantly contribute to its antiaging effect. Antioxidant effects of N-acetylserotonin (NAS), a melatonin precursor and metabolite, might predict its antiaging action as well. The antiaging effect of NAS was studied in female retired breeders and male C3H mice. Both NAS and melatonin administered with drinking water prolonged life span in male animals by about 20% versus control animals (p < 0.01) but did not affect the life span of female mice. Antioxidative activity was evaluated by determining the malonaldehyde + 4-hydroxynonenal (MDA + 4-HNE) and cellular glutathion peroxidase (GPx) levels in male, 11-month-old, C57B1/6J mice with very limited (if any) capacity to convert pineal NAS into melatonin. NAS increased the antioxidant capacity of kidney. Both NAS and melatonin (four weeks daily i.p. injections) increased the antioxidant capacity of brain as demonstrated by decreased MDA + 4-HNE and increased GPx levels. NAS-treated C57B1/6J mice experienced a weight loss of 9%, whereas the saline and melatonin groups only 3%. NAS- and melatonin-treated animals had healthy and luxuriant fur coats with some gray fur in the melatonin group; animals in the saline group had large areas of baldness. This study demonstrates, for the first time, the antiaging effect of NAS. This effect needs to be confirmed in animals with impaired capacity to convert NAS into melatonin.

Pierpaoli W, Maestroni GJ. Melatonin: a principal neuroimmunoregulatory and anti-stress hormone: its ANTI-AGING effects. Immunol Lett 1987, 16(3-4): 355-61.

Major environmental variables such as daily and seasonal changes of light and temperature regulate the daily circadian variations of synthesis and release of the pineal neurohormone N-acetyl-5-methoxytryptamine (melatonin). Melatonin has now been shown to be a potent immunoregulatory agent, and to be able to antagonize the immunosuppressive effects of acute anxiety stress in mice, as measured by antibody production, by thymus weight, and by the capacity of stressed- and evening-melatonin-treated mice to react against a lethal virus. Both psychogenic factors and infectious agents such as viruses can act as "stressors" and induce an immunosuppression. Their combination is a determinant for the course of infectious diseases and, perhaps, cancer. Circadian (evening) melatonin possesses thus the singular ability to up-regulate the immunosuppression of stressed mice. This effect of melatonin is not exerted directly on immunocompetent cells, but mediated via the endogenous opioid system upon antigen-activation of T cells. Melatonin being a short-lived hormone with negligible side-effects which is rapidly degraded and eliminated by the body, the use of melatonin offers a new approach to the physiological control of stress and stress-related infectious diseases. In addition, melatonin could be used for the potentiation of primary immunization (vaccination) against antigens of the most varied nature which do not evoke a robust or longlasting secondary (memory) response. The regulatory function of pineal melatonin is discussed also in relation to hematopoiesis, to its oncostatic effects, and to its possible dual role in reproduction physiology and generation of immunocompetence and tolerance during ontogeny.

Rattan SI. The nature of gerontogenes and vitagenes. ANTIAGING effects of repeated heat shock on human fibroblasts. Ann N Y Acad Sci 1998, 854:54-60

Our survival and the physical quality of life depends upon an efficient functioning of various maintenance and repair processes. This complex network of the so-called longevity assurance processes is composed of several genes, termed vitagenes. The homeodynamic property of living systems is a function of such a vitagene network. Because aging is characterized by the failure of homeodynamics, a decreased efficiency and accuracy of the vitagene network can transmutate it into a gerontogene network. It is not clear how various components of the vitagene network operate and influence each other in a concordant or a discordant manner. Experimental strategies through which this transmutation of vitagenes into virtual gerontogenes may be elucidated include induction of molecular damage, antisense intervention, and genetic screening for varied efficiencies of the members of the vitagene family. A reversal of this approach by maintaining or recovering the activity of vitagenes will lead to a delay of aging, a decreased occurrence of age-related diseases, and a prolongation of a healthy life span.

Rattan SIS. N-6-furfuryladenine (kinetin) as a potential ANTI-AGING molecule. Journal of Anti-Aging Medicine 2002, 5 (1): 113-116.

N-6-furfuryladenine (kinetin) is one of the cytokinin compounds whose anti-aging effects on plants, cultured human skin cells, and fruitflies have been reported. Its chemical structure, natural occurrence, and several biological effects are well documented. Although the exact mechanism of its action is not fully understood, kinetin appears to be a powerful natural antioxidant with pluripotent effects in protecting DNA and protein from oxidative and glyoxidative damage. Further applications of kinetin in health care and biomedicine need to be investigated thoroughly.

Regelson W, Franson R. Phospholipase A2 as a "death trigger" in the aging process. The use of PLA2 inhibitors as ANTIAGING substances. Ann N Y Acad Sci 1991, 621: 262-76.

Shimokawa I, Higami Y. A role for leptin in the ANTIAGING action of dietary restriction: a hypothesis. Aging (Milano) 1999, 11(6):380-2.

A neuroendocrine signal may play an important role in the antiaging action of dietary restriction (DR). Recent studies have suggested that falling leptin levels by starvation activate the hypothalamic-pituitary-adrenal axis, and suppress gonadal, somatotropic, and thyroid axes as a response for adaptation. Accumulated evidence indicates that similar hormonal changes also occur in DR rodents. In this article, we advance that a reduction in plasma leptin levels in DR rodents might be a critical neuroendocrine modulator in the antiaging action of dietary restriction.

Shimokawa I, Higami Y. Leptin and ANTI-AGING action of caloric restriction. J Nutr Health Aging, 2001;5(1):43-8.

Evolutional theories of aging and caloric restriction (CR) in animals predict the presence of neuroendocrine signals to divert the limited energy resources from energy-costly physiologic processes such as reproduction to those essential for survival in response to food shortage. The diversion of energy and subsequent molecular mechanisms might extend the lifespan. A growing body of evidence indicates that leptin, a peptide hormone secreted from adipocytes, has a key role in neuroendocrine adaptation against life-threatening stress such as fasting. The present review discusses the potential role of leptin in the anti-aging action of CR. Although several alternative signaling pathways might also mediate the anti-aging action of CR, leptin signaling could be a substantial pathway in the CR action. Research on neuroendocrine mechanisms of CR is warranted, because such efforts might provide clues to the regulation of the aging process in humans.

Svendsen L, Rattan SI, Clark BF. Testing garlic for possible ANTI-AGING effects on long-term growth characteristics, morphology and macromolecular synthesis of human fibroblasts in culture. Ethnopharmacol 1994, 43(2):125-33

The beneficial effects claimed for the use of garlic as a nutritional supplement include detoxification, antioxidation, antifungal activity, antibacterial activity, tumour suppression and, possibly, anti-ageing and rejuvenating effects. We have used the Hayflick system of cellular ageing in culture in order to test garlic for its anti-ageing effects on long-term growth characteristics, morphology and macromolecular synthesis of human skin fibroblasts. Our results show that an addition of garlic extract into the normal cell culture medium can support serial subculturing for over more than 55 population doublings in 475 days, and that this treatment has some youth-preserving, anti-ageing and beneficial effects on human fibroblasts in terms of maximum proliferative capacity and morphological characteristics. In comparison, similar or lesser doses of garlic extracts are growth inhibitory for cancerous cells that could not be grown over longer periods in the presence of garlic. To our knowledge, this is the first report of the effects of garlic on the long-term growth characteristics and macromolecular synthesis of normal human skin cells, the results of which have applications for both anti-ageing and anti-cancer research.

Yin D. Is carbonyl detoxification an important ANTI-AGING process during sleep? Med Hypotheses 2000, 54(4):519-22

Organisms living on the earth may undergo inevitable toxification by biological 'garbage', a variety of bio-metabolites. Such garbage includes a particularly large number of toxic carbonyls, such as alpha,beta-unsaturated carbonyls created by free radicals, glycation, and other post-translational side-reactions during various stresses and diseases. The accumulation of these toxic substances and their crosslinking products leads to the formation of different age pigments, such as lipofuscin, lens cataracts, and crosslinked collagen. The diurnal fluctuation in the concentration of the pineal gland hormone, melatonin, may be responsible for the 'cleaning activities' that reverse the covalently-bound semi-toxified proteins and nucleic acids. This toxification-cleaning cycle may explain the biochemical necessity for sleep of human and animals during aging.

Yu BP Approaches to ANTI-AGING intervention: the promises and the uncertainties. Mech Ageing Dev 1999, 111 (2-3): 73-87

Humans have long sought the elixir to long life. Today, although advances in our understanding of the aging process have given gerontologists new insights in potential anti-aging interventions, public demand for these interventions is outpacing our current knowledge. My presentation begins with a brief historical background that outlines some of the past and present approaches to anti-aging interventions. Using the dietary restriction paradigm as a prototype, discussions center on a three-pathway model that provides the bases to design effective interventions: (1) retardation of biological aging, (2) suppression of age-related disease, and (3) modulation of cross talk between (1) and (2). One other concept useful for discussion in relation to interventions is the enhancement of an organism's resistance to deter vulnerability to aging and disease. These models are best used to explain the efficacy of currently popular interventions such as antioxidant supplementation and hormone therapies. This presentation further highlights the promises that antioxidant supplements hold in warding off oxidative damage as well as their inherent problems and biological limitations. Also discussed here are the promises and uncertainties of anti-aging interventions by genetic manipulation, as seen in animal model studies, and prophylactic treatments targeted against disease, such as hormonal approaches using estrogen and DHEA, as well as other intervening measures.

Van Remmen H, Guo Z, Richardson A. The ANTI-AGING action of dietary restriction. Novartis Found Symp 2001, 235:221-30

Over 60 years ago, McCay's laboratory showed that dietary or calorie-restriction dramatically increased the lifespan of rats. Since then, numerous laboratories with a variety of strains of rats and mice have confirmed this initial observation and have shown that reducing calorie intake (without malnutrition) significantly increases both the mean and maximum survival of rodents. Currently, dietary restriction is the only experimental manipulation that has been shown to retard ageing of mammals. Although mechanism whereby dietary restriction retards ageing is currently unknown, much of the emerging data suggest that the calorie-restricted rodents live longer and age more slowly because they are more resistant to stress and have an enhanced ability to protect cells against damaging agents.

The scientific legitimacy of the term "anti-aging" is sometimes questioned because it is often associated with advertisements like these: