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Life Extension Magazine

LEF Magazine April 1998

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Life Extension magazine republishes abstracts on health and longevity topics in each issue, drawn from research papers originally published in science and medical journals throughout the world.

The Application of Vitamin C and E in Protecting Skin

Effectiveness of antioxidants (vitamin C and E) with and without sunscreens as topical photoprotectants.
Darr D Dunston S Faust H Pinnell S. Acta Derm Venereol (1996 Jul) 76(4):264-8

Considerable interest has been recently generated concerning the use of natural compounds, anti-oxidants in particular, in photoprotection. Two of the best known anti-oxidants are vitamins C and E, both of which have been shown to be somewhat effective in different models of photodamage. Very little has been reported, however, on the effectiveness of a combination of the two (known to be biologically the more relevant situation); nor have there been detailed studies on the ability of these antioxidants to augment commercial sunscreen protection against UV damage. We report that (in swine skin) vitamin C is capable of additive protection against acute UVB damage (sunburn cell formation) when combined with a UVB sunscreen. A combination of both vitamins E and C provided very good protection from a UVB insult, the bulk of the protection attributable to vitamin E. However, vitamin C is significantly better than vitamin E at protecting against a UVA-mediated phototoxic insult in this animal model, while the combination is only slightly more effective than vitamin C alone. When vitamin C or a combination of vitamin C and E is formulated with a commercial UVA sunscreen (oxybenzone), an apparently greater than additive protection is noted against the phototoxic damage. These results confirm the utility of anti-oxidants as photoprotectants but suggest the importance of combining the compounds with known sunscreens to maximize photoprotection.

Melatonin Suppresses UV-Induced Erythema

Suppression of UV-induced erythema by topical treatment with melatonin (N-acetyl-5-methoxytryptamine). A dose response study.
Bangha E Elsner P Kistler GS, Arch Dermatol Res (1996 Aug) 288(9):522-6

Oxygen-centred free radicals play an important role in the pathogenesis of acute and chronic UV-induced skin damage as well as in skin aging. In this double-blind randomized study the efficacy of topically applied melatonin (N-acetyl-5-methoxytryptamine), a potent free radical scavenger, in the suppression of UV-induced erythema was assessed. A group of 20 healthy volunteers were irradiated with 0.099 J/cm2 UVB on four 5-cm2 areas on the lower back and topically treated with various concentrations of melatonin (0.05, 0.1, 0.5%) in a nanocolloid gel as carrier or with carrier alone. The UV-induced erythema was examined 8 and 24 h after irradiation by visual scoring and chromametry. A distinct dose response relationship was observed between the topical dose of melatonin and the degree of UV-induced erythema. Significant differences (P < 0.05) were found in redness (chromameter a-value and visual scoring) 8 h after irradiation between the areas treated with melatonin at 0.5% and those treated with melatonin at 0.05% or with the carrier. These results might open a new approach in the prevention and control of free radical- influenced skin diseases.

Topical DHEA Inhibits Tumors

Dehydroepiandrosterone (DHEA) and 3 beta-methylandrost-5-en-17-one: inhibitors of 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12- O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin papilloma formation in mice.
Pashko LL Rovito RJ Williams JR Sobel EL Schwartz AG, Carcinogenesis (1984 Apr) 5(4):463-6

Long-term oral administration of the adrenal steroid, dehydroepiandrosterone (DHEA), has previously been shown to inhibit the development of spontaneous breast cancer and chemically induced lung and colon tumors in various mouse strains. Topical application of DHEA inhibits both 7,12-dimethylbenz[a]anthracene initiation and 12-O- tetradecanoylphorbol-13-acetate promotion of these tumors. The synthetic steroid, 3 beta-methylandrost-5-en-17-one, which, unlike DHEA, is not demonstrably estrogenic in the rat, also inhibits papilloma development.

Melatonin and The Inhibition of Fibroblasts

Effect of melatonin on normal and sclerodermic skin fibroblast proliferation.
Carossino AM Lombardi A Matucci-Cerinic M Pignone A Cagnoni M, Clin Exp Rheumatol (1996 Sep-Oct) 14(5):493-8

OBJECTIVE: We studied the effect of melatonin (MLT) (N-acetyl 5- methoxytryptamine) on the growth rate of normal skin fibroblasts and of fibroblasts from involved and apparently uninvolved skin of patients affected by systemic sclerosis (SSc). METHODS: The growth rate was evaluated on the basis of growth curves and a 3H-thymidine incorporation assay. RESULTS: Our results demonstrate that a dose of 200 micrograms/ml of MLT inhibits (> 80%) both control and SSc fibroblasts. Inhibition was dose-dependent and was greater than 70% for MLT concentrations of 100 micrograms/ml, 200 micrograms/ml and 400 micrograms/ml. 3H-thymidine incorporation was correlated with the effect on the growth curves (81% at 200 micrograms/ml of MLT). In contrast, at a low dosage of 6 micrograms/ml, MLT exerted a stimulatory effect on cell proliferation in all the cell lines analyzed. Cell viability was not affected by MLT at any of the concentrations tested. A recovery study indicated that replacement of MLT-containing medium with MLT-free medium resulted in a re-establishment of cell growth. CONCLUSIONS:These results suggest that MLT, at higher dosages, is a potent inhibitor of the proliferation of fibroblasts derived from the skin of healthy and SSc patients.

Topical Vitamin E's Impact on Photocarcinogenesis

Importance of the form of topical vitamin E for prevention of photocarcinogenesis.
Gensler HL Aickin M Peng YM Xu M, Nutr Cancer (1996) 26(2):183-91.

With increasing solar ultraviolet (UV)-B radiation reaching the Earth's surface and the incidence of skin cancer rising steadily, there is an ever-increasing need to determine agents that modulate photocarcinogenesis and to understand the mechanisms underlying this modulation. Our laboratory has demonstrated that topical application of the dl-alpha-tocopherol form of vitamin E to mice prevents skin cancer and the immunosuppression induced by UVB irradiation. However, dl-alpha-tocopherol has limited stability at room temperature. The current study was designed to ask whether the thermostable esters of vitamin E, alpha-tocopheryl acetate, or alpha-tocopheryl succinate prevent skin cancer and immunosuppression induced in mice by UV radiation. In the alpha-tocopheryl acetate study, skin cancers developed in 70% of UVB-irradiated control mice and in 90%, 73%, and 90% of mice receiving topical applications of 12.5, 25, and 50 mg of dl-alpha-tocopheryl acetate, respectively. In the alpha-tocopheryl succinate study, skin cancer developed in 59.3% of control UVB- irradiated mice and in 82%, 100%, and 81.5% of mice treated with 2.5, 12.5, and 25 mg d-alpha-tocopheryl succinate, respectively. Thus neither alpha-tocopheryl acetate nor alpha-tocopheryl succinate prevented photocarcinogenesis. At 12.5 and 25 mg/treatment, alpha- tocopheryl acetate and alpha-tocopheryl succinate, respectively, enhanced photocarcinogenesis (p = 0.0114 and 0.0262, respectively, log rank test). On the basis of high-performance liquid chromatography analysis at 16-17 weeks after the first vitamin E treatment, the esterified forms of vitamin E applied epicutaneously accumulated in the skin, but the levels of free alpha-tocopherol remained low. Neither alpha-tocopheryl acetate nor alpha-tocopheryl succinate prevented the induction by UV radiation of immunosusceptibility to implanted syngeneic antigenic UV-induced tumor cells. Thus alpha-tocopheryl acetate or alpha-tocopheryl succinate not only failed to prevent photocarcinogenesis, but may have enhanced to process. Considering that alpha-tocopherol esters are included in many skin lotions, cosmetics, and sunscreens, further studies are needed to determine the conditions under which topical alpha-tocopheryl acetate and alpha-tocopheryl succinate enhance photocarcinogenesis.

Transdermal Delivery of Melatonin

Preliminary evaluation of transdermal delivery of melatonin in human subjects. Lee BJ Parrott KA Ayres JW Sack RL, Res Commun Mol Pathol Pharmacol (1994 Sep) 85(3):337-46

A transdermal delivery device (TDD)1 was applied to four human subjects to investigate whether melatonin (MT) could penetrate through human skin. The TDD (total surface area of 3.80 cm2) was applied to the forearm of each subject. Plasma MT concentrations increased above baseline in approximately 2-4 hours, although steady state was not achieved in the 8-hour study period. Intersubject variation of plasma MT among four subjects was noted. Urinary excretion of 6-sulphatoxymelatonin (6-STMT), a major metabolite of MT in humans, increased as plasma MT concentrations increased. Cumulative amounts of urinary 6-STMT increased over a 6-hour period when the TDD was applied and were three times greater than in controls. The urinary excretion rate of 6-STMT was statistically correlated with plasma MT concentration among subjects (r2 = 0.77). These data suggest that the urinary excretion rate of 6-STMT can be used as an index of MT plasma concentrations in human subjects. An intersubject variability in both plasma MT concentration and urinary excretion rate of 6-STMT was noted; still, MT can be delivered transdermally in human subjects.

DHEA and Thermal Skin Injury

Dehydroepiandrosterone reduces progressive dermal ischemia caused by thermal injury.
Araneo BA Ryu SY Barton S Daynes RA, J Surg Res (1995 Aug) 59(2):250-62

Progressive ischemia and necrosis of the skin following thermal injury are reduced by postburn administration of the steroid hormone dehydroepiandrosterone (DHEA). Thermally injured animals were provided with a subcutaneous injection of DHEA, or a related species of steroid hormone, at various times after burning. During the 96 hr following administration of the scald burn, tissue necrosis was closely monitored. Subcutaneous administration of DHEA at approximately 1 mg/kg/day achieved optimal protection against the development of progressive dermal ischemia. DHEA, 17 alpha-hydroxy- pregnenolone, 16 alpha-bromo-DHEA, and androstenediol each demonstrated, a similar level of protection. Other forms of steroids, including DHEA sulfate, androstenedione, 17 beta-estradiol, or dihydrotestosterone, exhibited no protective effect under the conditions tested. Additionally, intervention therapy with DHEA could be initiated up to 4 hr, but not 6 hr, after burn without a marked reduction in therapeutic benefit. Examination of the microvasculature of thermally injured dorsal skin suggested that postburn intervention with DHEA, either directly or indirectly, maintained a normal architecture in most of the dermal capillaries and venules within burn-exposed tissue. These findings suggest that systemic intervention therapy of burn patients with DHEA or a similar acting steroid hormone may be useful in preventing the progressive tissue destruction caused by progressive ischemia.

High Bioavailability of DHEA

High bioavailability of dehydroepiandrosterone administered percutaneously in the rat.
Labrie C Flamand M Belanger A Labrie F, J Endocrinol (1996 Sep) 150 Suppl:S107-18

Dehydroepiandrosterone (DHEA) administered percutaneously by twice daily application for 7 days to the dorsal skin of the rat stimulates an increase in ventral prostate weight with approximately one third the potency of the compound given by subcutaneous injection. The doses required to achieve a 50% reversal of the inhibitory effect of orchiectomy are approximately 3 and 1 mg respectively. By the oral route, on the other hand. DHEA has only 10-15% of the activity of the compound given percutaneously. Taking the bioavailability obtained by the subcutaneous route as 100%, it is estimated that the potencies of DHEA by the percutaneous and oral routes are approximately 33 and 3% respectively. Similar ratios of activity were obtained when dorsal prostate and seminal vesicle weight were used as parameters of androgenic activity. When examined on an estrogen-sensitive parameter, namely uterine weight in ovariectomized rats, the stimulatory effect of DHEA was much less potent than its androgenic activity measured in the male animal, a 50% reversal of the inhibitory effect of ovariectomy on uterine weight being observed at the 3 and 30 mg doses of DHEA administered by the subcutaneous and percutaneous routes respectively. When measured on uterine weight, percutaneous DHEA thus shows a 10% potency compared with the subcutaneous route. The sulfate of DHEA (DHEA-S), on the other hand, was approximately 50% as potent as DHEA at increasing ventral prostate weight after subcutaneous or percutaneous administration. When the effect was measured on dorsal prostate and seminal vesicle weight, percutaneous DHEA-S had 10-25% of the activity of DHEA. DHEA decreased serum LH levels in ovariectomized animals, an effect which was completely reversed by treatment with the antiandrogen flutamide. On the other hand, flutamide had no significant effect on the increase in uterine weight caused by DHEA, thus suggesting a predominant estrogenic effect of DHEA at the level of the uterus and an estrogenic effect on the feedback control of LH secretion. The present data show a relatively high bioavailability of percutaneous DHEA as measured by its androgenic and/or estrogenic biological activity in well-characterized peripheral target intracrime tissues in the rat.

Vitamin E's Effect on Scar Tissue

Topical vitamin E as a cause of erythema multiforme-like eruption.
Saperstein H Rapaport M Rietschel RL , Arch Dermatol (1984 Jul) 120(7):906-8

The topical use of vitamin E on scar tissue resulted in a generalized erythema multiforme reaction in two patients. Patch tests with vitamin E oil showed positive local reactions in both.

Exercise Intensity and Longevity in Men

Exercise intensity and longevity in men. The Harvard Alumni Health Study [see comments]
Lee IM Hsieh CC Paffenbarger RS Jr, JAMA (1995 Apr 19) 273(15):1179-84

OBJECTIVE--To examine the independent associations of vigorous (> or = 6 resting metabolic rate [MET] score) and nonvigorous (< 6 MET score) physical activity with longevity. DESIGN--Prospective cohort study, following up men from 1962 or 1966 through 1988. SETTING/PARTICIPANTS--Subjects were Harvard University alumni, without self-reported, physician-diagnosed cardiovascular disease, cancer, or chronic obstructive pulmonary disease (n = 17,321). Men with a mean age of 46 years reported their physical activities on questionnaires at baseline. MAIN OUTCOME MEASURE--All-cause mortality (3728 deaths). RESULTS--Total energy expenditure and energy expenditure from vigorous activities, but not energy expenditure from nonvigorous activities, related inversely to mortality. After adjustment for potential confounders, the relative risks of dying associated with increasing quintiles of total energy expenditure were 1.00 (referent), 0.94, 0.95, 0.91 and 0.91, respectively (P [trend] < .05). The relative risks of dying associated with less than 630, 630 to less than 1680, 1680 to less than 3150, 3150 to less than 6300, and 6300 or more kJ/wk expended on vigorous activities were 1.00 (referent), 0.88, 0.92, 0.87, and 0.87, respectively (P [trend] = .007). Corresponding relative risks for energy expended on nonvigorous activities were 1.00 (referent), 0.89, 1.00, 0.98, and 0.92, respectively (P [trend] = .36). Analyses of vigorous and nonvigorous activities were mutually adjusted. Among men who reported only vigorous activities (259 deaths), we observed decreasing age- standardized mortality rates with increasing activity (P = .05); among men who reported only nonvigorous activities (380 deaths), no trend was apparent (P = .99). CONCLUSIONS--These data demonstrate a graded inverse relationship between total physical activity and mortality. Furthermore, vigorous activities but not nonvigorous activities were associated with longevity. These findings pertain only to all-cause mortality; nonvigorous exercise has been shown to benefit other aspects of health. Comment in: ACP J Club 1995 Sep-Oct;123(2):52-3. Comment in: JAMA 1995 Oct 11;274(14):1132-3

Exercise and Mortality in The Elderly

Does exercise reduce mortality rates in the elderly? Experience from the Framingham Heart Study.
Sherman SE D'Agostino RB Cobb JL Kannel WB, Am Heart J (1994 Nov) 128(5):965-72

Regular physical activity decreases the mortality rate in middle-aged men and probably in middle-aged women. It is unknown whether this is also true in the elderly. We studied 285 men and women aged 75 years or older who were free of cardiovascular disease. Subjects were ranked by baseline physical activity levels and grouped into quartiles. After adjustments were made for cardiac risk factors, chronic obstructive pulmonary disease, and cancer, women in the second most active quartile had a much lower risk of mortality at 10 years (relative risk 0.24, 95% confidence interval 0.12 to 0.51). There was no statistically significant difference in men. There appeared to be an excess of sudden cardiac deaths in the most active women, although this group still lived longer than the least active women. We conclude that women aged 75 years or older who are more active live longer. This benefit may be attenuated in those who are extremely active.

Physical Activity and Women

Physical activity and mortality in women in the Framingham Heart Study
Sherman SE D'Agostino RB Cobb JL Kannel WB, In: Am Heart J (1994 Nov) 128(5):879-84

Men who are more active live longer, but it is not clear if the same is true for women. We monitored 1404 women aged 50 to 74 who were free of cardiovascular disease. We assessed physical activity levels and ranked subjects into quartiles. After 16 years, 319 (23%) women had died. The relative risk of mortality, compared to the least active quartile, was as follows: second quartile, 0.95 (95% confidence interval [CI] 0.72 to 1.26); third quartile, 0.63 (95% CI 0.46 to 0.86); most active quartile, 0.67 (95% CI 0.48 to 0.92). The relative risks were not changed by adjustment for cardiac risk factors, chronic obstructive pulmonary disease, or cancer or by excluding all subjects who died in the first 6 years (to eliminate occult disease at baseline). There was no association between activity levels and cardiovascular morbidity or mortality. We conclude that women who were more active lived longer; this effect was not the result of decreased cardiovascular disease.

EDTA Chelation Therapy and Arteriosclerosis

Arteriographic findings in EDTA chelation therapy on peripheral arteriosclerosis [see comments]
Sloth-Nielsen J Guldager B Mouritzen C Lund EB Egeblad M Norregaard O Jorgensen SJ Jelnes R, Am J Surg (1991 Aug) 162(2):122-5

In a randomized, double-blind, controlled study, 153 patients with claudication were each given either 20 infusions of Na2EDTA or 20 infusions of saline. Walking distances and ankle/brachial indices were measured before, during, and after treatment. In 30 patients, angiograms and transcutaneous oxygen tensions were obtained before, during, and after treatment. The patients' subjective evaluations of the effect of treatment were also recorded. It is concluded that EDTA chelation therapy has no effect in patients with intermittent claudication in the legs caused by arteriosclerosis. Comment in: Am J Surg 1993 Sep;166(3):316, Registry Numbers: 60-00-4 (Edetic Acid) 7782-44-7 (Oxygen)

Resuscitative Hypothermia

Resuscitative hypothermia.
Marion DW Leonov Y Ginsberg M Katz LM Kochanek PM Lechleuthner A Nemoto EM Obrist W Safar P Sterz F Tisherman SA White RJ Xiao F Zar H, Crit Care Med (1996 Feb) 24(2 Suppl):S81-9

Resuscitative (postinsult) hypothermia is less well studied than protective-preservative (pre- and intra-arrest) hypothermia. The latter is in wide clinical use, particularly for protecting the brain during cardiac surgery. Resuscitative hypothermia was explored in the 1950s and then lay dormant until the 1980s when it was revived. This change occurred through the discoveries of brain damage mitigating effects after cardiac arrest in dogs, and after forebrain ischemia in rats, of mild (34 degrees C) hypothermia (which is safe), and of benefits derived from moderate hypothermia (30 degrees C) after traumatic brain injury or focal brain ischemia in various species. The idea that protection-preservation or resuscitation by hypothermia is mainly explained by its ability to reduce cerebral oxygen demand has been replaced by an increasingly documented synergism of many beneficial mechanisms. Deleterious chemical cascades during and after these insults are suppressed even by mild hypothermia. Prolonged moderate hypothermia carries some risks, e.g., arrhythmias, infection and coagulopathies. These side effects need further study. In global brain ischemia, protective-preservative mild hypothermia provides lasting mitigation of brain damage. Resuscitative mild hypothermia, however, may be beneficial in terms of long-term outcome or may merely delay the inevitable loss of selectively vulnerable neurons. Even if the latter is true, mild hypothermia may extend the therapeutic window for other interventions. This extension of the therapeutic window requires further documentation. After normothermic cardiac arrest of 11 mins in dogs, mild resuscitative hypothermia from 15 mins to 12 hours after reperfusion plus cerebral blood flow promotion normalized functional recovery with the least histologic damage seen thus far. Optimal duration of, and rewarming methods from, resuscitative hypothermia need clarification. The earliest possible induction of mild hypothermia after cardiac arrest seems desirable. Head-neck surface cooling alone is too slow. Among many clinically feasible rapid cooling methods, carotid cold flush and peritoneal cooling look promising. After traumatic brain injury or focal brain ischemia, which seem to still benefit from even later cooling, surface cooling methods may be adequate. Resuscitative hypothermia after cardiac arrest, traumatic brain injury, or focal brain ischemia should be considered for clinical trials.

Modern Resuscitation Techniques

On the history of modern resuscitation.
Safar P, Crit Care Med (1996 Feb) 24(2 Suppl):S3-11

The development of modern cardiopulmonary-cerebral resuscitation (CPCR) has given every person the ability to challenge death anywhere. Despite sparks of knowledge and occasional applications of possibly effective lifesaving efforts since antiquity, the possibility to reverse acute terminal states or clinical death by modern, physiologically sound, and effective measures did not come about until around 1900 inside hospitals, and around 1960 outside hospitals. Additional potentially effective cerebral resuscitation, research since around 1970, may be taken to clinical trials before the year 2000. The history of resuscitation medicine around 1900, when many opportunities to assemble existing bits of knowledge into an effective system were missed, should be a warning for those individuals who will lead CPCR beyond the year 2000. History has shown the need for continuing communication and collaboration among investigators of different countries, and between laboratory researchers, clinicians of various disciplines, and prehospital rescuers. The lessons learned from history, for research challenges in the near future, include: a) the development of ultra-advanced life support to be initiated outside the hospital, to bridge cardiopulmonary resuscitation (CPR)-resistant cases to definitive cardiac procedures in the hospital; and b) cerebral resuscitation to complete recovery after 10 to 15 mins of normothermic cardiac arrest without blood flow. Both challenges above will require research projects at multiple levels--from the molecular and cellular levels, to the use of small and large animal models (with organs' and organisms' process and outcome evaluations), to studies of patients and communities. Beyond the year 2000, resuscitation research might become more challenging and cost-effective in the area of multiple trauma, which concerns the young and fit. Research challenges concerning brain trauma, uncontrolled hemorrhagic shock, and "suspended animation" for delayed resuscitation have their own histories, and are not covered here. The author apologizes for not having recognized many important contributors to the history of CPCR because of space constraints or lack of knowledge about such contributions. Input on this subject from readers of this paper is hereby invited.



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